WO2025264672A1 - Inhibitors of mobilized colistin resistance enzyme (mcr-1) and methods of use thereof - Google Patents

Inhibitors of mobilized colistin resistance enzyme (mcr-1) and methods of use thereof

Info

Publication number
WO2025264672A1
WO2025264672A1 PCT/US2025/033970 US2025033970W WO2025264672A1 WO 2025264672 A1 WO2025264672 A1 WO 2025264672A1 US 2025033970 W US2025033970 W US 2025033970W WO 2025264672 A1 WO2025264672 A1 WO 2025264672A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
chlorophenyl
biphenyl
cdd
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/033970
Other languages
French (fr)
Inventor
Timothy Palzkill
Martin Matzuk
Srinivas CHAMAKURI
Isabel MATERON
Moh SATTAR
Zhizeng SUN
Sreenivasa Ramana
Nicholas MSZAR
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Baylor College of Medicine
Original Assignee
Baylor College of Medicine
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Baylor College of Medicine filed Critical Baylor College of Medicine
Publication of WO2025264672A1 publication Critical patent/WO2025264672A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C

Definitions

  • Polymyxins are cationic polypeptides that act by binding to the lipid A moiety of bacterial lipopolysaccharide (LPS) and subsequently disrupting the bacterial membrane.
  • LPS bacterial lipopolysaccharide
  • Acquired and chromosome-encoded resistance to colistin has been reported among Gram-negative bacteria and some species, such as Neisseria spp., are intrinsically resistant to colistin.
  • the most common mechanism of acquired resistance involves modification of the LPS component of the outer membrane. Specifically, resistance occurs due to modification of the 1 and 4’ phosphate groups of lipid A to neutralize the negative charge and reduce binding of the positively charged colistin.
  • the phosphates are modified with 4-amino-arabinose by the aminoarabinose transferase ArnT or by addition of phosphoethanolamine (PEA) by PEA transferase enzymes.
  • PEA phosphoethanolamine
  • Chromosome encoded and acquired resistance to polymyxins is associated with mutations found in genes for two-component regulatory systems and result in - 1 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) expression of the transferase enzymes that modify LPS.
  • ArnT is a membrane protein with a periplasmic domain and is a glycosyltransferase.
  • the PEA transferases also have a membrane-spanning domain and a periplasmic catalytic domain.
  • the catalytic domain of the NmEptA and EptC PEA transferases have a similar structure and are members of the sulfatase group with a fold similar to alkaline phosphatase.
  • MCR-1 plasmid- encoded LPS-modifying enzyme
  • the disclosure provides a compound of Formula (I), or a salt, solvate, stereoisomer, or isotopologue thereof, wherein R 1 , R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , L 1 , L 2 , and X 1 are defined elsewhere herein: .
  • composition comprising at least one compound of the carrier or excipient.
  • disclosure provides a method of treating, preventing, and/or ameliorating a bacterial infection in a subject.
  • the method comprises administering to the subject at least one compound of the disclosure, or a pharmaceutical composition thereof, and at least one polymyxin antibiotic, or an analogue or derivative thereof.
  • FIG.1 shows the structure of lipid A of E. coli showing reaction catalyzed by PEA transferases such as MCR-1.
  • FIGs.2A-2B show the structure of NmEptA solved by X-ray crystallography.
  • FIG 2A shows a ribbon diagram of NmEptA.
  • Dodecyl- ⁇ -D-maltoside (DDM) shown as spheres.
  • FIG. 2B shows the active site with DDM. Key residues are labeled.
  • the catalytic zinc is shown as a sphere.
  • Helices PH2 and PH2’ are at the border of the active site and membrane domain.
  • FIG.3 shows the DECL process.
  • FIG.4 shows sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS- PAGE) of purified fractions of full length MCR-1 (62 kDa).
  • FIG.5A shows schematic of enzyme-catalyzed removal of phosphoethanolamine - 3 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) from fluorescently labeled phosphotidylethanolamine substrate (NDB-PEA) to create product NDB-DG.
  • FIG.5B shows thin-layer chromatography (TLC) of reaction products. Positions of NBD-PEA and NDB-DG are labeled. CT is a no enzyme control TLC.
  • FIG.6 shows compounds initially identified compounds CDD-1794 and CDD-1938.
  • FIGs.7A-7F show spot test for E. coli growth with colistin and CDD-1938. Overnight (O/N) cultures of E.
  • FIG.7B shows 25 ⁇ M CDD-1938 with no colistin.
  • FIG.7C shows .0.8 ⁇ g/ml colistin, no CDD-1938.
  • FIG.7D shows 0.8 ⁇ g/ml colistin with 3.1 ⁇ M CDD-1938.
  • FIG.7E shows 0.8 ⁇ g/ml colistin with 6.3 ⁇ M CDD-1938.
  • FIG.7F shows 0.8 ⁇ g/ml colistin with 12.5 ⁇ M CDD-1938.
  • FIGs.8A-8B docking results of CDD-1794 and CDD-1938 to MCR-1 homology model.
  • FIG.8A shows CDD-1794 docked in MCR-1 model.
  • CDD-1794 is in a pocket adjacent to the active site Zn and catalytic Thr285.
  • FIG.8B shows CDD-1938 docked in MCR-1 homology model. Without being bound by theory, CDD-1938 is postulated to occupy the same site as CDD-1794.
  • FIG.9 shows structure-activity relationships for CDD-1938. Schematic of the DECL hit based on DNA sequencing. The linker, cycle 1, building block position (C1). Cycle 2 (C2) and 3 (C3) building block positions are shown.
  • B-M are molecular analogs of CDD-1938.
  • FIG.10 shows colistin MIC values for E. coli expressing MCR-1 in the presence of inhibitor compounds of the disclosure. MICs shown on Y-axis in log2 scale. Compound concentrations indicated on X-axis. Compounds are indicated in the inset.
  • FIG.11 shows spot test assay for CDD compounds against MCR-1 mediated colistin resistant clinical isolates. The top row shows the spot test for agar plates containing 0.8 ⁇ g/ml colistin.
  • the bottom two rows show spot test results using agar plates containing 0.8 mg/ml colistin and 12.5 ⁇ M CDD compound. Each strain was tested in duplicate. The spots on each plate are a non-diluted overnight culture on the far right and 10-fold serial dilutions proceeding right to left. The strains corresponding to each row of spots are labeled. WT-1 and WT-2 represent the duplicates of E. coli XL1-Blue containing MCR-1. The clinical strains and duplicates are labeled. Each column of plates corresponds to the compound tested as indicated below the columns. The columns are arranged from most potent compound on the right to least potent on the left.
  • FIG.12 shows structure-activity relationships for analogs based on the high potency - 4 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) CDD-2901 and CDD-2847 compounds. Compound names and potency based on comparison to colistin alone in the spot assay are shown. Cytotoxicity as indicated by IC 50 for HepG2 cells is shown for select compounds.
  • FIG.13 shows a summary of structure-activity relationships based on analogs of CDD-1794.
  • FIG.14 Catalytically functional MCR-1 is necessary for protection against colistin in E. coli. Time-kill curve of E.
  • FIGs.15A-15D Structures of DNA-encoded chemical library (DECL) hits and analogs with activity against MCR-1. Activity of the compounds with or without colistin against E. coli/WT MCR-1 growth was tested using the spot assay and minimum inhibitory concentration (MIC) method, respective values determined at 12.5 ⁇ g/mL compound concentration are indicated under each compound structure. For the spot assay method, colistin was set at 0.32 ⁇ g/mL and scored based on the fold difference (X) between growth with colistin alone vs colistin/compound combination; while for MIC, colistin was tested from 0-32 ⁇ g/mL and 12.5 ⁇ g/mL compound.
  • MIC minimum inhibitory concentration
  • FIG.15A Structure of DECL screening hit CDD-1938. This racemic mixture was identified through affinity-based selection of a DECL of 2 million compounds against purified WT MCR-1 His-tagged enzyme.
  • FIG.15B Structure of DECL screening hit CDD-3358. This compound was also identified through affinity-based selection of a DECL of 2 million compounds against purified WT MCR-1 enzyme, and a truncated version of the CDD-3358 compound, CDD-1794, was synthesized and tested due to difficulties in resynthesizing CDD-3358.
  • FIG.15C Structures of potent inhibitor analogs derived from the original DECL hit, CDD-1938.
  • FIG.15D Structure of a potent inhibitor analog derived from the original DECL truncated hit, CDD-1794. This lead inhibitor evolved from a series of analogs that were - 5 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) optimized by modifying the C1, C2 and C3 building blocks to enhance bioactivity of CDD- 1794.
  • FIGs.16A-16B MCR-1 protects E.
  • FIG.16A DNA- encoded chemical library (DECL) screening hits block the catalytic activity of MCR-1 and resensitize bacteria to colistin killing. Spot assay experiments for E. coli containing wild- type MCR-1 (1) and T285A MCR-1 (2) expressed from a plasmid also conferring chloramphenicol (Cm) resistance were performed. E.
  • coli strains were grown overnight in LB media containing Cm (12.5 ⁇ g/mL), normalized, diluted (10-1 through 10-6) and spotted on LB media containing Cm (12.5 ⁇ g/mL): media control, or LB + Cm with a sub-inhibitory concentration of colistin sodium methane sulfonate (0.32 ⁇ g/mL), or with a high (12.5 ⁇ M) concentration of inhibitor only and with both 0.32 ⁇ g/mL colistin and low (3.125 ⁇ M), medium (6.25 ⁇ M) or high (12.5 ⁇ M) concentrations of inhibitors CDD-1938 and CDD- 1794. All inhibitor only controls were similar to the representative inhibitor, CDD-1938, and media only controls shown in the chart.
  • FIG.17 Optimized inhibitors show improved potency against MCR-1 and resensitize bacteria to colistin killing. Spot assay experiments for E.
  • E. coli containing wild-type MCR-1 (1) and T285A MCR-1 (2) expressed from a plasmid also conferring chloramphenicol (Cm) resistance were performed.
  • E. coli strains were grown overnight in LB media containing Cm (12.5 ⁇ g/mL), normalized, diluted (10-1 through 10-6) and spotted on LB media containing Cm (12.5 ⁇ g/mL): media control, or LB + Cm with a sub-inhibitory concentration of colistin sodium methane sulfonate (0.32 ⁇ g/mL), or with a high (12.5 ⁇ M) concentration of inhibitor only and with both 0.32 ⁇ g/mL colistin and high (12.5 ⁇ M) concentrations of inhibitors: CDD-2750, CDD-2847, CDD-3002, CDD-2902, CDD-3003, and CDD-3356.
  • FIGs.18A-18B Colistin MIC values for E. coli expressing MCR-1 in the absence and presence of inhibitor compounds.
  • FIG.18A Colistin sulfate MIC values in the absence and presence of inhibitor compounds from screening hits and their optimized analogs for E.
  • FIG. 18B A graphic representation of the MICs shown on the Y-axis in log2 scale and compound concentrations are indicated on the X-axis. Compounds tested are indicated in the inset. Error bars represent standard error mean.
  • FIG.19 MCR-1 inhibitors are active against Enterobacterales clinical isolates containing MCR-1 and MCR-2.
  • FIGs.20A-20B Time-kill curve for E.
  • FIG.20A Time-kill analysis of various treatments with inhibitor CDD-3003 as described in the inset.
  • FIG.20B Time-kill analysis of various treatments with inhibitor CDD-3356 as described in the inset.
  • Unidirectional error bars for clarity, represent the standard error mean.
  • FIGs.21A-21C Comparison of MCR-1 and its variants using AlphaFold2.
  • FIG.22 Catalytically functional MCR-1 is necessary for protection against colistin in E. coli. Time-kill curve of E.
  • FIG.23 Optimized inhibitor shows activity against select mcr-1+ E. coli clinical isolates and partially resensitizes these bacteria to colistin killing. Spot assay experiments for laboratory E. coli containing wild-type MCR-1 (1) and T285A MCR-1 (2) expressed from a plasmid also conferring chloramphenicol (Cm) resistance as controls and mcr-1+ E. coli clinical isolates were performed. E. coli clinical isolates: #107 (3), #109 (4), #240 (5), #6770 (6), #9824 (7), #9991 (8) and #10618 (9) were obtained.
  • the laboratory strains were grown overnight in LB media containing Cm (12.5 ⁇ g/mL) and E. coli clinical isolates were grown in LB media; all strains were normalized, diluted (10-1 through 10-6) and spotted on LB agar containing Cm (12.5 ⁇ g/mL) or LB agar as a media control, or LB + Cm with a sub- inhibitory concentration of colistin sodium methane sulfonate (0.32 ⁇ g/mL), or with a high (12.5 ⁇ M) concentration of inhibitor only and with both 0.32 ⁇ g/mL colistin and high (12.5 ⁇ M) concentrations of inhibitors, CDD-2750. All media only and inhibitor only controls were similar among the clinical isolates shown in the chart.
  • FIGs.24A-24B Time-kill curve analysis for E. coli expressing WT MCR-1 against 4 ⁇ g/mL colistin sulfate (CS) in the presence and absence of the racemic mixture, CDD-3366, and its S-enantiomer, CDD-3356.
  • FIG.24A Various concentrations of racemic mixture, CDD-3366, combined with 4 ⁇ g/mL CS were tested against E.
  • FIG.24B Various concentrations of S-enantiomer, CDD-3356, combined with 4 - 8 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) ⁇ g/mLCS were tested against E. coli/WT MCR-1 in CAMH + Cm (12.5 ⁇ g/mL) grown at 37°C for 4.5 hours. Data represents one independent experiment performed in duplicate. Unidirectional error bars, for clarity, represent the standard error mean.
  • FIGs.25A-25B Structural comparison of MCR-1, NmEptA and PmrC.
  • FIG.25B Superposition of the Alphafold2 predicted full-length MCR-1 from E. coli and PmrC from A.
  • FIG.26 Analog series of chemotype 1, CDD-1938, showing varied bioactivity. Spot assay score defines the difference in growth between colistin-only treatment vs colistin/MCR-1 inhibitor treatment; it is described as a fold difference. Data shown here are representative of multiple (2-4) experiments. Where there are ranges, both values were identified several times in multiple experiments.
  • FIG.27 Analog series of chemotype 2, CDD-1794, showing varied bioactivity.
  • a range of “about 0.1% to about 5%” or “about 0.1% to 5%” should be interpreted to include not just about 0.1% to about 5%, but also the individual values (e.g., 1%, 2%, 3%, and 4%) - 9 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) and the sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range.
  • the statement “about X to Y” has the same meaning as “about X to about Y,” unless indicated otherwise.
  • Polymyxin E also known as colistin
  • polymyxin B are the most studied and clinically used forms. They act predominantly by targeting the anionic lipid A component of the lipopolysaccharide (LPS) present in the outer membrane (OM) of Gram- negative bacteria causing membrane destabilization, OM and inner membrane (IM) permeability, leakage of cellular contents, and ultimately cell death.
  • LPS lipopolysaccharide
  • OM outer membrane
  • IM inner membrane
  • colistin resistance has already been identified in carbapenemase-producing, multidrug-resistant (MDR) or extensively drug-resistant (XDR) Gram-negative bacteria on the CDC and WHO priority threat lists. Colistin resistance is primarily mediated through a reduction of the electrostatic attraction between colistin and the Gram-negative OM.
  • intrinsic polymyxin resistance is associated with the constitutive expression of chromosomal genes encoding transferase enzymes, such as ArnT, EptA (also known as PmrC), and EptC.
  • transferase enzymes such as ArnT, EptA (also known as PmrC), and EptC.
  • Aminoarabinose transferase, ArnT modifies the 1’- and 4’- anionic phosphate groups of the glucosamine moieties of lipid A in LPS with cationic 4- amino-4-deoxy-L-arabinose (L-Ara4N) and the phosphoethanolamine (pEtN) transferase, EptA, modifies the phosphate with a cationic pEtN.
  • mcr-1 an ortholog of eptA (pmrC)
  • pmrC ortholog of eptA
  • pEtN transferase confers colistin resistance through the addition of pEtN from phosphatidylethanolamine, a naturally occurring phospholipid, to the 1’- or 4’- phosphate group of lipid A component of LPS as it is trafficked through the IM on the way to the OM.
  • MDR multidrug-resistant
  • mcr-1 + strains and restore colistin efficacy such as CRISPR/CAS-based tools to eliminate mcr-1 strains, mcr-1 plasmid conjugation inhibitors, MCR inhibitors, novel polymyxin derivatives, combination therapy using various antibacterial agents and non-antibiotic compounds.
  • CRISPR/CAS-based tools to eliminate mcr-1 strains, mcr-1 plasmid conjugation inhibitors, MCR inhibitors, novel polymyxin derivatives, combination therapy using various antibacterial agents and non-antibiotic compounds.
  • Described herein is an approach to extend the efficacy of colistin using combination therapy with a synergizing bioactive partner, in this case, an inhibitor of the important resistance determinant MCR-1.
  • a synergizing bioactive partner in this case, an inhibitor of the important resistance determinant MCR-1.
  • MCR-1 the important resistance determinant
  • a DNA-encoded chemical libraries DECL
  • DECLs consist of very large collections of compounds, each coupled to distinctive DNA tags serving as amplifiable identification barcodes, which permit the retrieval and identification of binding compounds after screening.
  • the colistin/inhibitor combination operates through self-promoted uptake of colistin as previously described, facilitating the entry of the lipophilic inhibitor across the OM and into the periplasm where it reaches the enzyme target, MCR-1, located in the IM.
  • MCR-1 has been shown to protect the IM and confer resistance to polymyxins by modifying high levels of LPS with pEtN at the IM, thus repelling colistin from the IM.
  • the inhibitor blocks MCR-1 activity allowing colistin to then, permeabilize the IM, trigger bacterial lysis and cause death.
  • the anti-infective efficacy of the two antibiotic/inhibitor - 13 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) combinations was also assessed using TKCs, where the rate of bactericidal killing was followed over a range of inhibitor concentrations and fixed colistin concentration.
  • the TKC data for E. coli/MCR-1 indicate that both chemotypes, at their most effective concentrations (12.5 ⁇ M), in combination with colistin, achieve complete bacterial killing by as early as 1.5 hours (CDD-3356/colistin) or 1 hour (CDD-3003/colistin) upon administration, which is up to 2.5 hours or 4 hours earlier to killing with colistin alone (FIGs.20A-20B).
  • CDD-3356 and CDD-3003 both display a dose-dependent behavior, although it is more pronounced for CDD-3356.
  • the best effective inhibitor concentrations, 6.25 and 12.5 ⁇ M, combined with colistin are close to the goal to develop small-molecule compounds that inhibit MCR-1 in the 1 ⁇ g/mL (2 ⁇ M) range and effectively kill E. coli/MCR-1.
  • the antibacterial activity of these compounds also extends to MDR mcr-1+ K. pneumoniae clinical isolates by reducing growth by 16-fold (CDD-3356) or by 8-fold (CDD-3003), as measured by the microdilution method (Table 9).
  • Inhibitors within the CDD-3003 chemotype series combined with colistin although cytotoxic, also demonstrated inhibitory growth effects ranging from 10 2 -10 5 -fold against mcr-2+ E. coli and multiple mcr- 1+ E. coli clinical strains and, at best, 10-fold against mcr-1+ K. pneumoniae compared to colistin alone as measured using the spot assay (FIG.19).
  • the lower range observed in MIC and spot assay values for the colistin/inhibitor combination among some of the clinical isolates tested, particularly K. pneumoniae may be due to poor compound penetration.
  • acyl refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom.
  • the carbonyl carbon atom is bonded to a hydrogen forming a "formyl” group or is bonded to another carbon atom, which can be part of an alkyl, aryl, aralkyl cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group or the like.
  • An acyl group can include 0 to about 12, 0 to about 20, or 0 to about 40 additional carbon atoms bonded to the carbonyl group.
  • An acyl group can include double or triple bonds within the meaning herein.
  • An acryloyl group is an example of an acyl group.
  • An acyl group can also include heteroatoms within the meaning herein.
  • a nicotinoyl group (pyridyl-3-carbonyl) is an example of an acyl group within the meaning herein.
  • Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and the like.
  • alkenyl refers to straight and branched chain and cyclic alkyl groups as defined herein, except that at least one double bond exists between two carbon atoms.
  • alkenyl groups have from 2 to 40 carbon atoms, or 2 to about 20 carbon atoms, or 2 to 12 carbon atoms or, in some embodiments, from 2 to 8 carbon atoms.
  • alkoxy refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined herein.
  • An alkoxy group can include about 1 to about 12, about 1 to about 20, or about 1 to about 40 carbon atoms bonded to the oxygen atom, and can further include double or triple - 15 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) bonds, and can also include heteroatoms.
  • an allyloxy group or a methoxyethoxy group is also an alkoxy group within the meaning herein, as is a methylenedioxy group in a context where two adjacent atoms of a structure are substituted therewith.
  • alkyl refers to straight chain and branched alkyl groups and cycloalkyl groups having from 1 to 40 carbon atoms, 1 to about 20 carbon atoms, 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms.
  • straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n- butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups.
  • branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups.
  • alkyl encompasses n-alkyl, isoalkyl, and anteisoalkyl groups as well as other branched chain forms of alkyl.
  • Representative substituted alkyl groups can be substituted one or more times with any of the groups listed herein, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
  • alkynyl refers to straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms.
  • alkynyl groups have from 2 to 40 carbon atoms, 2 to about 20 carbon atoms, or from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to – C ⁇ CH, -C ⁇ C(CH3), -C ⁇ C(CH2CH3), -CH2C ⁇ CH, -CH2C ⁇ C(CH3), and -CH2C ⁇ C(CH2CH3) among others.
  • antibiotic refers to a compound or composition that kills or reduces the viability of a microorganism or inhibits the growth or proliferation of a microorganism.
  • amine refers to primary, secondary, and tertiary amines having, e.g., the formula N(group)3 wherein each group can independently be H or non-H, such as alkyl, aryl, and the like.
  • amino group refers to a substituent of the form -NH2, - NHR, -NR 2 , -NR 3 + , wherein each R is independently selected, and protonated forms of each, - 16 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) except for -NR3 + , which cannot be protonated. Accordingly, any compound substituted with an amino group can be viewed as an amine.
  • An “amino group” within the meaning herein can be a primary, secondary, tertiary, or quaternary amino group.
  • An "alkylamino” group includes a monoalkylamino, dialkylamino, and trialkylamino group.
  • aralkyl refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein.
  • Representative aralkyl groups include benzyl and phenylethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl.
  • Aralkenyl groups are alkenyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein.
  • aryl refers to cyclic aromatic hydrocarbon groups that do not contain heteroatoms in the ring.
  • Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, a phenyl group substituted at any one or more of 2-, 3-, 4-, 5-, or 6-positions of the phenyl ring, or a naphthyl group substituted at any one or more of 2- to 8-positions thereof.
  • the term “bacteria”, as used herein, refers to both prokaryotic and archaebacteria cellular organisms. “Bacteria” are unicellular microorganisms which have cell walls but lack organelles and an organized nucleus, including some that can cause disease.
  • bacterial colony refers to growths of bacteria accumulated in distinct segments on solid materials or surfaces including agar plates, which in some cases includes cells from bacterial infection of a subject or host. A bacterial colony is derived from a common mother cell.
  • biofilm refers to a chemical matrix produced to protect a bacteria or microorganism population. Biofilms are generally characterized as adhering to a surface and having a thin, slimy texture. Biofilms may grow in or on medical devices or prosthetic joints, or at other sites in tissue and organs.
  • composition or “pharmaceutical composition” refers to a mixture of at least one compound described herein with a pharmaceutically acceptable carrier.
  • the pharmaceutical composition facilitates administration of the compound to a - 17 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) patient or subject.
  • Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary and topical administration.
  • cycloalkyl refers to cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
  • a “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal's health continues to deteriorate.
  • a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal's state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal's state of health.
  • the terms "effective amount,” “pharmaceutically effective amount” and “therapeutically effective amount” refer to a nontoxic but sufficient amount of an agent to provide the desired biological result.
  • haloalkyl group includes mono-halo alkyl groups, poly- halo alkyl groups wherein all halo atoms can be the same or different, and per-halo alkyl - 18 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro.
  • haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3- difluoropropyl, perfluorobutyl, and the like.
  • heteroaryl refers to aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S; for instance, heteroaryl rings can have 5 to about 8-12 ring members.
  • a heteroaryl group is a variety of a heterocyclyl group that possesses an aromatic electronic structure.
  • a heteroaryl group designated as a C 2 -heteroaryl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth.
  • a C 4 -heteroaryl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth.
  • Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolin
  • heteroarylalkyl refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined herein.
  • heterocyclylalkyl refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group as defined herein is replaced with a bond to a heterocyclyl group as defined herein.
  • heterocyclyl alkyl groups include, but are not limited to, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl.
  • heterocyclyl refers to aromatic and non-aromatic ring compounds containing three or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, and S.
  • a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or if polycyclic, any combination thereof.
  • heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members.
  • a heterocyclyl group designated as a C2-heterocyclyl can be a 5-ring with two - 20 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth.
  • a C 4 -heterocyclyl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms.
  • a heterocyclyl ring can also include one or more double bonds.
  • a heteroaryl ring is an embodiment of a heterocyclyl group.
  • the phrase "heterocyclyl group" includes fused ring species including those that include fused aromatic and non-aromatic groups. For example, a dioxolanyl ring and a benzdioxolanyl ring system (methylenedioxyphenyl ring system) are both heterocyclyl groups within the meaning herein.
  • the phrase also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. Heterocyclyl groups can be unsubstituted, or can be substituted as discussed herein.
  • Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquino
  • substituted heterocyclyl groups can be mono-substituted or substituted more than once, such as, but not limited to, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or 6- substituted, or disubstituted with groups such as those listed herein.
  • hydrocarbon or “hydrocarbyl” as used herein refers to a molecule or functional group that includes carbon and hydrogen atoms. The term can also refer to a molecule or functional group that normally includes both carbon and hydrogen atoms but wherein all the hydrogen atoms are substituted with other functional groups.
  • (C 1 -C 4 )hydrocarbyl means the hydrocarbyl group can be methyl (C 1 ), ethyl (C2), propyl (C3), or butyl (C4), and (C0-Cb)hydrocarbyl means in certain embodiments there is no hydrocarbyl group.
  • the term "independently selected from” as used herein refers to referenced groups being the same, different, or a mixture thereof, unless the context clearly indicates otherwise.
  • the phrase "X 1 , X 2 , and X 3 are independently selected from noble - 21 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) gases" would include the scenario where, for example, X 1 , X 2 , and X 3 are all the same, where X 1 , X 2 , and X 3 are all different, where X 1 and X 2 are the same but X 3 is different, and other analogous permutations.
  • the term “infection” as used herein refers to the onset of a disease by one or more pathogenic bacteria, including but not limited to Gram negative bacteria.
  • the term "monovalent” as used herein refers to a substituent connecting via a single bond to a substituted molecule. When a substituent is monovalent, such as, for example, F or Cl, it is bonded to the atom it is substituting by a single bond.
  • organic group refers to any carbon-containing functional group. Examples can include an oxygen-containing group such as an alkoxy group, aryloxy group, aralkyloxy group, oxo(carbonyl) group; a carboxyl group including a carboxylic acid, carboxylate, and a carboxylate ester; a sulfur-containing group such as an alkyl and aryl sulfide group; and other heteroatom-containing groups.
  • patient refers to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein.
  • the patient, subject or individual is a human.
  • pharmaceutically acceptable refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid.
  • inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric (including sulfate and hydrogen sulfate), and phosphoric acids (including hydrogen phosphate and dihydrogen phosphate).
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, malonic, saccharin, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2- hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic,
  • Suitable pharmaceutically acceptable base addition salts of compounds described herein include, for example, ammonium salts, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts.
  • Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N'-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared from the corresponding compound by reacting, for example, the appropriate acid or base with the compound.
  • the term "pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound described herein within or to the patient such that it may perform its intended function.
  • a pharmaceutically acceptable material, composition or carrier such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound described herein within or to the patient such that it may perform its intended function.
  • Such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound(s) described herein, and not injuri
  • materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and - 23 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydro
  • pharmaceutically acceptable carrier also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound(s) described herein, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions.
  • the "pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound(s) described herein.
  • Other additional ingredients that may be included in the pharmaceutical compositions used with the methods or compounds described herein are known in the art and described, for example in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.
  • the term “prosthesis” as used herein refers to an artificial body part.
  • room temperature refers to a temperature of about 15 °C to 28 °C.
  • solvent refers to a liquid that can dissolve a solid, liquid, or gas.
  • Non-limiting examples of solvents are silicones, organic compounds, water, alcohols, ionic liquids, and supercritical fluids.
  • substantially refers to a majority of, or mostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%.
  • substantially free of can mean having none or having a trivial amount of, such that the amount of material present does not affect the material properties of the composition including the material, such that the composition is about 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to, or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less.
  • substantially free of can mean having a trivial amount of, such that a composition is about 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to, or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less, or about 0 wt%.
  • substituted as used herein in conjunction with a molecule or an organic - 24 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) group as defined herein refers to the state in which one or more hydrogen atoms contained therein are replaced by one or more non-hydrogen atoms.
  • functional group or “substituent” as used herein refers to a group that can be or is substituted onto a molecule or onto an organic group.
  • substituents or functional groups include, but are not limited to, a halogen (e.g., F, Cl, Br, and I); an oxygen atom in groups such as hydroxy groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboxylate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxyamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups.
  • a halogen e.g., F, Cl, Br, and I
  • an oxygen atom in groups such as hydroxy groups, al
  • Non-limiting examples of substituents that can be bonded to a substituted carbon (or other) atom include F, Cl, Br, I, OR, OC(O)N(R) 2 , CN, NO, NO2, ONO2, azido, CF3, OCF3, R, O (oxo), S (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R) 2 , SR, SOR, SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2)0- 2N(R)C(O)R, (CH2)0-2N(R)N(R)2, N(R)N(R)C(O)R, N(R)
  • a “therapeutic” treatment is a treatment administered to a subject who exhibits signs of pathology, for the purpose of diminishing or eliminating those signs.
  • treatment or “treating” is defined as the application or administration of a therapeutic agent, i.e., a compound or compounds as described herein (alone or in combination with another pharmaceutical agent), to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell line from a patient (e.g., for diagnosis or ex vivo applications), who has a condition contemplated herein or a symptom of a condition contemplated herein, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect a condition contemplated herein, or the symptoms of a condition contemplated herein.
  • the compound of Formula (I) is a compound of Formula (Ia): of is a compound of certain embodiments, the compound of Formula (I) is a compound of In certain embodiments, the compound of Formula (I) is a compound of In certain embodiments, the compound of Formula (I) is a compound of Formula (If): (If).
  • the compound of Formula (I) is a compound of Formula (Ia- certain embodiments, the compound of Formula (I) is a compound of Formula certain embodiments, the compound of Formula (I) - 30 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) is a compound of Formula In certain embodiments, the compound of Formula (I) is a compound of In certain embodiments, the compound of Formula (I) is a compound of 1). In certain embodiments, the compound of Formula (I) is a : certain embodiments, the compound of Formula (I) is a compound of Formula (Id-1): (Id-1).
  • the compound of Formula (I) is a compound of Formula certain embodiments, the compound of Formula (I) is a compound of In certain embodiments, the compound of Formula (I) is a compound of In certain - 31 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) embodiments, the compound of Formula (I) is a compound of Formula (If-1): (If-1).
  • the compound of Formula (I) is a compound of Formula (If- , wherein R 5a , R 5b , R 5c , R 5d , and R 5e are of H, halogen, CN, NO 2 , OR A , , substituted C6-C10 aryl, and optionally substituted C 2 -C 10 heteroaryl.
  • R 5a , R 5b , R 5d , and R 5e are each independently selected from of H, ha A A B logen, CN, NO2, OR , N(R )(R ), optionally substituted C 1 -C 6 alkyl, optionally substituted C 6 -C 10 aryl, and optionally substituted C2-C10 heteroaryl.
  • at least one of R 5a , R 5b , R 5c , R 5d , and R 5e is phenyl.
  • the phenyl in R 5a , R 5b , R 5c , R 5d , or R 5e is substituted with at least one selected from the group consisting of OH, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkyl, and C1-C6 haloalkyl.
  • R 5a is H. In certain embodiments, R 5a is CH3. In certain embodiments, R 5a is Ph. In certain embodiments, R 5a . In certain embodiments, R 5a . In certain embodiments, R 5a . In certain embodiments, R 5a is . In certain embodiments, R 5a .
  • R 5b is H. In certain embodiments, R 5b is CH3. In certain embodiments, R 5b is Ph. In certain embodiments, R 5b . In certain embodiments, R 5b . In certain embodiments, R 5b . In certain embodiments, R 5b In certain embodiments, . In certain embodiments, R 5c is H. In certain embodiments, R 5c is embodiments, R 5c is Ph. In certain embodiments, R 5c is . In certain embodiments, R 5c . In certain embodiments, R 5c is . In certain embodiments, R 5c . In certain embodiments, certain embodiments, certain embodiments, R 5d is H.
  • R 5d is CH 3 . In certain embodiments, R 5d is Ph. In certain embodiments, R 5d . In certain embodiments, R 5d . In certain embodiments, R 5d . In certain embodiments, R 5d . In certain embodiments, R 5e R 5e is CH 3 . In R 5e is Ph. In certain embodiments, R 5e . In certain embodiments, . In certain embodiments, R 5e . In certain embodiments, R 5e is - 33 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) .
  • R 6a , R 6b , R 6c , R 6d , and R 6e are each independently selected of H, optionally substituted C 1 -C 6 alkyl, optionally substituted C2-C6 haloalkyl, optionally substituted C6-C10 aryl, optionally - 34 - 55708207.3
  • R 6a , R 6b , R 6c , R 6d , and R 6e are each independently selected of H, optionally substituted C 1 -C 6 alkyl, optionally substituted C2-C6 haloalkyl, optionally substituted C6-C10 aryl, optionally - 34 - 55708207.3
  • R 6a is H. In certain embodiments, R 6a is F. In certain embodiments, R 6a is Cl. In certain embodiments, R 6b is H. In certain embodiments, R 6b is F. In certain embodiments, R 6b is Cl. In certain embodiments, R 6c is H. In certain embodiments, R 6c is F. In certain embodiments, R 6c is Cl. In certain embodiments, R 6d is H. In certain embodiments, R 6d is F. In certain embodiments, R 6d is Cl. In certain embodiments, R 6e is H. In certain embodiments, R 6e is F. In certain embodiments, R 6e is Cl.
  • one of R 6a , R 6b , R 6c , R 6d , and R 6e is F or Cl.
  • R 7a , R 7b , R 7c , and R 7d is H. In certain embodiments, at least two of R 7a , R 7b , R 7c , and R 7d are H. In certain embodiments, at least three of R 7a , R 7b , R 7c , and R 7d are H. In certain embodiments, each of R 7a , R 7b , R 7c , and R 7d are H. In certain embodiments, R 7e is H. In certain embodiments, R 7e is CH3. In certain embodiments, R 7e is CH2OCH3. In certain embodiments, R 7e is . In certain R 7e . In R 7f is H.
  • R 7f is CH 3 . In certain embodiments, R 7f is CH2OCH3. In certain embodiments, R 7f is . In certain . In R 8 is phenyl optionally substituted with at least one halogen. In certain embodiments, R 8 is phenyl. In certain embodiments, R 8 is 4-chlorophenyl. In certain embodiments, R 8 is 4-fluorophenyl. In certain embodiments, L 3 is a bond. In certain embodiments, L 3 is –(CH2)-. In certain embodiments, L 3 is –(CHCH 3 )-. In certain embodiments, L 3 is –[CH(CH 2 OCH 3 )]CH 2 - . In certain embodiments, L 3 .
  • R 9 is optionally substituted indolyl. In certain embodiments, R 9 is optionally substituted naphthyl. In certain embodiments, the phenyl is optionally substituted with at least one C 1 -C 6 haloalkyl. In certain embodiments, the haloalkyl is CF3. In certain embodiments, R 9 is . In certain embodiments, R 9 9 . In certain embodiments, R is - 41 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) . is H. In certain embodiments, the combination of L 3 -R 9 is . In certain embodiments, the combination of L 3 -R 9 is .
  • the combination of L 3 -R 9 In certain embodiments, the combination of L 3 -R 9 . In certain embodiments, the combination of L 3 -R 9 . In certain embodiments, the combination of L 3 -R 9 . In certain embodiments, the combination of L 3 -R 9 . In certain embodiments, the combination of L 3 -R 9 . In certain embodiments, the combination of L 3 -R 9 In certain embodiments, the In certain embodiments, the certain embodiments, the combination of L 3 -R 9 is certain embodiments, the In certain embodiments, the - 42 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) certain embodiments, the combination of L 3 -R 9 is . In certain embodiments, the combination of L 3 -R 9 .
  • the combination of L 3 -R 9 In certain embodiments, the certain embodiments, the combination of L 3 -R 9 is certain embodiments, the In certain embodiments, the combination of L 3 -R 9 .
  • the compound is selected from the group consisting of: 2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(cyclopropyl(phenyl)methyl)-N-methyl-1H- benzo[d]imidazole-5-carboxamide; (R)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(cyclopropyl(phenyl)methyl)-N-methyl- 1H-benzo[d]imidazole-5-carboxamide; (S)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(cyclopropyl(phenyl)methyl)-N-methyl-1H- benzo[d]imidazole-5-carboxamide; 1-benzyl-N-methyl-2-(4-phenylthiazol-2-yl)-1H-benzo[d]imidazole-5-carboxamide; 2-(4-(4-chlorophen
  • At least one additional agent suitable for treating, preventing, and/or ameliorating a bacterial infection is selected from the group consisting of a polymyxin, aminoglycoside, ⁇ -lactam (e.g., penicillin, cephalosporin, or carbapenem), monobactam, fluoroquinolone, sulfonamide, tetracycline, and macrolide.
  • the additional agent suitable for treating, preventing, and/or ameliorating a bacterial infection is at least one selected from the group consisting of colistin (polymyxin E), polymyxin B, amikacin, ampicillin, amoxicillin, aminoglycoside, azithromycin, aztreonam, carbapenem, cefepime, cefiderocol, cefotaxime, ceftriaxone, ceftaroline, ceftazidime, ceftobiprole, ceftolozane, ciprofloxacin, clindamycin, dalbavancin, daptomycin, doxycycline, ertapenem, fluoroquinolone, gentamicin, imipenem, levofloxacin, linezolid, meropenem, minocycline, mupirocin, oritavancin, piperacillin, streptogramin, sulbactam,
  • colistin
  • compositions containing the compound(s) described herein include a pharmaceutical composition comprising at least one compound as described herein and at least one pharmaceutically acceptable carrier.
  • the composition is formulated for an administration route such as oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal, intravesical, intrapulmonary, intraduodenal, - 57 - 55708207.3
  • a pharmaceutical composition comprising a compound provided herein and further comprising a pharmaceutically acceptable excipient.
  • Preparation of Compounds Compounds described herein can be prepared by the general schemes described herein, using the synthetic method known by those skilled in the art. The following examples illustrate non-limiting embodiments of the compound(s) described herein and their preparation.
  • the compounds described herein can possess one or more stereocenters, and each stereocenter can exist independently in either the (R) or (S) configuration.
  • compounds described herein are present in optically active or racemic forms. It is to be understood that the compounds described herein encompass racemic, optically-active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein.
  • Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase.
  • a mixture of one or more isomer is utilized as the therapeutic compound described herein.
  • compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis and/or separation of a mixture of enantiomers and/ or diastereomers.
  • Resolution of compounds and isomers thereof is achieved by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.
  • the methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), solvates, amorphous phases, and/or pharmaceutically acceptable salts of compounds having the structure of any compound(s) described herein, as well as metabolites and active metabolites of these compounds having the same type of activity.
  • Solvates include water, ether (e.g., tetrahydrofuran, methyl tert-butyl ether) or alcohol (e.g., ethanol) solvates, acetates and the like.
  • the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, and ethanol.
  • the - 58 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) compounds described herein exist in unsolvated form.
  • the compound(s) described herein can exist as tautomers. All tautomers are included within the scope of the compounds presented herein.
  • compounds described herein are prepared as prodrugs.
  • a “prodrug” refers to an agent that is converted into the parent drug in vivo.
  • a prodrug upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound.
  • a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.
  • sites on, for example, the aromatic ring portion of compound(s) described herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the aromatic ring structures may reduce, minimize or eliminate this metabolic pathway.
  • the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a deuterium, a halogen, or an alkyl group.
  • Compounds described herein also include isotopically-labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds described herein include and are not limited to 2 H, 3 H, 11 C, 13 C, 14 C, 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, and 35 S.
  • isotopically-labeled compounds are useful in drug and/or substrate tissue distribution studies.
  • substitution with heavier isotopes such as deuterium affords greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements).
  • substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • Isotopically-labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.
  • the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • the compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein and as described, for example, in Fieser & Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley - 59 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4 th Ed., (Wiley 1992); Carey & Sundberg, Advanced Organic Chemi st ry 4th Ed.
  • Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed.
  • each protective group is removable by a different means.
  • Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal.
  • protective groups are removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and/or oxidative conditions.
  • Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and are used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile.
  • Carboxylic acid and hydroxy reactive moieties are blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl, in the presence of amines that are blocked with acid labile groups, such as t-butyl carbamate, or with carbamates that are both acid and base stable but hydrolytically removable.
  • carboxylic acid and hydroxy reactive moieties are blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids are blocked with base labile groups such as Fmoc.
  • Carboxylic acid reactive moieties are protected by conversion to simple ester compounds as exemplified herein, which include conversion to alkyl esters, or are blocked with oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while co- - 60 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) existing amino groups are blocked with fluoride labile silyl carbamates.
  • Allyl blocking groups are useful in the presence of acid- and base- protecting groups since the former are stable and are subsequently removed by metal or pi-acid catalysts.
  • an allyl-blocked carboxylic acid is deprotected with a palladium-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups.
  • Yet another form of protecting group is a resin to which a compound or intermediate is attached. As long as the residue is attached to the resin, that functional group is blocked and does not react. Once released from the resin, the functional group is available to react.
  • blocking/protecting groups may be selected from allyl, benzyl (Bn), benzyloxycarbonyl (Cbz), allyloxycarbonyl (Alloc), methyl, ethyl, t-butyl, t- butyldimethylsilyl (TBDMS), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), t-butyloxycarbonyl (Boc), para-methoxybenzyl (PMB), triphenylmethyl (trityl), acetyl, and fluorenylmethoxycarbonyl (FMOC).
  • Bn benzyl
  • Cbz benzyloxycarbonyl
  • Alloc allyloxycarbonyl
  • the disclosure provides a method of treating, preventing, and/or ameliorating a bacterial infection in a subject.
  • the method comprises administering to the subject at least one compound of the disclosure or the pharmaceutical composition of the disclosure.
  • the method comprises administering to the subject at least one polymyxin antibiotic, or an analogue or derivative thereof.
  • the disclosure provides a method of sensitizing a bacterial colony to at least one antibiotic polypeptide.
  • the method comprises contacting the bacterial colony with at least one compound of the disclosure or the pharmaceutical composition of the disclosure.
  • antibiotic polypeptide is colistin (polymyxin E).
  • polymyxin antibiotic is polymyxin B.
  • the antibiotic polypeptide is a defensin.
  • the antibiotic polypeptide comprises about 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, 200, 300, or 500 amino acids.
  • the antibiotic polypeptide is a defensin.
  • the - 61 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) antibiotic polypeptide has a charge of about +1, +2, +3, +4, +5, +10, +15, +20, +25, or +30 at a pH of about 7.4.
  • the bacterial infection or bacterial colony comprises a bacterial species selected from the group consisting of: Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus lugdenensis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus saprophyticus, Staphylococcus simulans, Staphylococcus warnerii, Staphylococcus capitis, Staphylococcus caprae, Staphylococcus pettenkoferi, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus pneumoniae, Group C streptococci, Streptococcus constellatus, Enterococcus faecalis, Enterococcus faecium, Corynebacterium jeikeium, Lactobacillus acidophilus, Listeria monocytogenes, Escher
  • the method further comprises administering at least one additional antibiotic.
  • the additional antibiotic is at least one selected from the group consisting of a aminoglycoside, ⁇ -lactam (e.g., penicillin, cephalosporin, or carbapenem), monobactam, fluoroquinolone, sulfonamide, tetracycline, and macrolide.
  • the additional antibiotic is at least one selected from the group consisting of amikacin, ampicillin, amoxicillin, aminoglycoside, azithromycin, aztreonam, carbapenem, cefepime, cefiderocol, cefotaxime, ceftriaxone, ceftaroline, ceftazidime, ceftobiprole, ceftolozane, ciprofloxacin, clindamycin, dalbavancin, daptomycin, doxycycline, ertapenem, fluoroquinolone, gentamicin, imipenem, levofloxacin, linezolid, meropenem, minocycline, mupirocin, oritavancin, piperacillin, streptogramin, sulbactam, tedizolid, telavancin, tigecycline, ticarcillin, tobramycin, trimethoprim/sul
  • the bacterial infection is a persistent or antibiotic resistant - 62 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) bacterial infection.
  • formation of a bacterial biofilm is at least partially prevented or inhibited.
  • the infection occurs on a prosthesis or an implant.
  • the prosthesis selected from the group consisting of a knee prosthesis, a hip prosthesis, elbow prosthesis, ankle prosthesis, shoulder prosthesis, and spine prosthesis.
  • the subject is a mammal. In certain embodiments, the mammal is a human.
  • the methods described herein include administering to the subject a therapeutically effective amount of at least one compound described herein, which is optionally formulated in a pharmaceutical composition.
  • a therapeutically effective amount of at least one compound described herein present in a pharmaceutical composition is the only therapeutically active compound in a pharmaceutical composition.
  • the method further comprises administering to the subject an additional therapeutic agent that treats a disease state.
  • administering the compound(s) described herein to the subject allows for administering a lower dose of the additional therapeutic agent as compared to the dose of the additional therapeutic agent alone that is required to achieve similar results in treating a disease state in the subject.
  • the compound(s) described herein enhance(s) the activity of the additional therapeutic compound, thereby allowing for a lower dose of the additional therapeutic compound to provide the same effect.
  • the compound(s) described herein and the therapeutic agent are co-administered to the subject.
  • the compound(s) described herein and the therapeutic agent are coformulated and co-administered to the subject.
  • the subject is a mammal.
  • the mammal is a human Combination Administration and Treatment
  • a synergistic effect is observed when a compound as described herein is administered with one or more additional therapeutic agents or compounds.
  • a synergistic effect may be calculated, for example, using suitable methods such as, for example, the Sigmoid-E max equation (Holford & Scheiner, 1981, Clin. Pharmacokinet. 6:429-453), the equation of Loewe additivity (Loewe & Muischnek, 1926, Arch. Exp. Pathol - 63 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) Pharmacol.114:313-326) and the median-effect equation (Chou & Talalay, 1984, Adv. Enzyme Regul.22:27-55).
  • Each equation referred to above may be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination.
  • the corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively.
  • Administration/Dosage/Formulations The regimen of administration may affect what constitutes an effective amount.
  • the therapeutic formulations may be administered to the subject either prior to or after the onset of a disease state. Further, several divided dosages, as well as staggered dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection. Further, the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.
  • compositions described herein to a patient may be carried out using known procedures, at dosages and for periods of time effective to treat a disease state in the patient.
  • An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the state of the disease or disorder in the patient; the age, sex, and weight of the patient; and the ability of the therapeutic compound to treat a disease state in the patient.
  • Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
  • a non-limiting example of an effective dose range for a therapeutic compound described herein is from about 1 and 5,000 mg/kg of body weight/per day.
  • One of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions described herein may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level depends upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or - 64 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts.
  • a medical doctor e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle.
  • compositions described herein are formulated using one or more pharmaceutically acceptable excipients or carriers.
  • pharmaceutical compositions described herein comprise a therapeutically effective amount of a compound described herein and a pharmaceutically acceptable carrier.
  • the carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition.
  • Prolonged absorption of the injectable compositions may be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.
  • the compositions described herein are administered to the - 65 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) patient in dosages that range from one to five times per day or more.
  • the compositions described herein are administered to the patient in range of dosages that include, but are not limited to, once every day, every two, days, every three days to once a week, and once every two weeks.
  • the compound(s) described herein for administration may be in the range of from about 1 ⁇ g to about 10,000 mg, about 20 ⁇ g to about 9,500 mg, about 40 ⁇ g to about 9,000 mg, about 75 ⁇ g to about 8,500 mg, about 150 ⁇ g to about 7,500 mg, about 200 ⁇ g to about 7,000 mg, about 350 ⁇ g to about 6,000 mg, about 500 ⁇ g to about 5,000 mg, about 750 ⁇ g to about 4,000 mg, about 1 mg to about 3,000 mg, about 10 mg to about 2,500 mg, about 20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 30 mg to about 1,000 mg, about 40 mg to about 900 mg, about 50 mg to about 800 mg, about 60 mg to about 750 mg, about 70 mg to about 600 mg, about 80 mg to about 500 mg, and any and all whole or partial increments therebetween.
  • the dose of a compound described herein is from about 1 mg and about 2,500 mg. In some embodiments, a dose of a compound described herein used in compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg.
  • a dose of a second compound as described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof.
  • the compound(s) described herein can be administered to a - 66 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) subject in an amount ranging from about 0.01 mg/kg to about 200 mg/kg, or about 0.5 mg/kg to about 190 mg/kg, or about 0.75 mg/kg to about 180 mg/kg, or about 1 mg/kg to about 170 mg/kg, or about 1.5 mg/kg to about 160 mg/kg, or about 2 mg/kg to about 150 mg/kg, or about 2.5 mg/kg to about 140 mg/kg, or about 3 mg/kg to about 130 mg/kg, or about 3.5 mg/kg to about 120 mg/kg, or about 4 mg/kg to about 110 mg/kg, or about 4.5 mg/kg to about 100 mg/kg, or about 5 mg/kg to about 95 mg/kg, or about 5.5 mg/kg to about 90 mg/kg, or about 6 mg/kg to about 85 mg/kg, or about 6.5 mg/kg to about 80 mg
  • the compound(s) described herein can be administered to a subject in an amount that is less than, equal to, or greater than about 0.01 mg/kg, 0.05 mg/kg, 0.1 mg/kg, 0.25 mg/kg, 0.5 mg/kg, 0.75 mg/kg, 1 mg/kg, 1.5 mg/kg, 2 mg/kg, 2.5 mg/kg, 3 mg/kg, 3.5 mg/kg, 4 mg/kg, 4.5 mg/kg, 5 mg/kg, 5.5 mg/kg, 6 mg/kg, 6.5 mg/kg, 7 mg/kg, 7.5 mg/kg, 8 mg/kg, 8.5 mg/kg, 9 mg/kg, 9.5 mg/kg, 10 mg/kg, 12 mg/kg, 14 mg/kg, 16 mg/kg, 18 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 55 mg/kg, 60 mg/kg, 65 mg/kg, 70 mg/kg, 75 mg/kg, 80 mg
  • a composition as described herein is a packaged pharmaceutical composition
  • Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art.
  • the pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like. They may also be combined where desired with other active agents, e.g., other analgesic agents.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like.
  • other active agents e.g., other analgesic agents.
  • the compounds for use in the compositions described herein can be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.
  • transdermal e.g., sublingual, lingual, (trans)buccal, (trans)urethral
  • vaginal e.g., trans- and perivaginally
  • intravesical, intrapulmonary, intraduodenal, intragastrical intrathecal
  • compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions described herein are not limited to the particular formulations and compositions that are described herein.
  • compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets.
  • excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate.
  • the tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.
  • the compound(s) described herein can be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., polyvinylpyrrolidone, hydroxypropylcellulose or hydroxypropyl methylcellulose); fillers (e.g., cornstarch, lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrates (e.g., sodium starch glycollate); or wetting agents (e.g., sodium lauryl sulphate).
  • binding agents e.g., polyvinylpyrrolidone, hydroxypropylcellulose or hydroxypropyl methylcellulose
  • fillers e.g., cornstarch, lactose, microcrystalline cellulose or calcium phosphate
  • the tablets may be coated using suitable methods and coating materials such as OPADRYTM film - 68 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) coating systems available from Colorcon, West Point, Pa. (e.g., OPADRYTM OY Type, OYC Type, Organic Enteric OY-P Type, Aqueous Enteric OY-A Type, OY-PM Type and OPADRYTM White, 32K18400).
  • suitable methods and coating materials such as OPADRYTM film - 68 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) coating systems available from Colorcon, West Point, Pa. (e.g., OPADRYTM OY Type, OYC Type, Organic Enteric OY-P Type, Aqueous Enteric OY-A Type, OY-PM Type and OPADRYTM White, 32K18400).
  • Liquid preparation for oral administration may be in the form of solutions, syrups or suspensions
  • the liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxy benzoates or sorbic acid).
  • suspending agents e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats
  • emulsifying agent e.g., lecithin or acacia
  • non-aqueous vehicles e.g., almond oil, oily esters or ethyl alcohol
  • preservatives e.g., methyl or propyl p-hydroxy benzoates or sorbic acid.
  • Compositions as described herein can be prepared, packaged, or sold in a
  • Compressed tablets may be prepared by compressing, in a suitable device, the active ingredient in a free-flowing form such as a powder or granular preparation, optionally mixed with one or more of a binder, a lubricant, an excipient, a surface active agent, and a dispersing agent. Molded tablets may be made by molding, in a suitable device, a mixture of the active ingredient, a pharmaceutically acceptable carrier, and at least sufficient liquid to moisten the mixture.
  • Pharmaceutically acceptable excipients used in the manufacture of tablets include, but are not limited to, inert diluents, granulating and disintegrating agents, dispersing agents, surface-active agents, disintegrating agents, binding agents, and lubricating agents.
  • Suitable dispersing agents include, but are not limited to, potato starch, sodium starch glycollate, poloxamer 407, or poloxamer 188.
  • One or more dispersing agents can each be individually present in the composition in an amount of about 0.01% w/w to about 90% w/w relative to weight of the dosage form.
  • One or more dispersing agents can each be individually present in the composition in an amount of at least, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w/w relative to weight of the dosage form.
  • Surface-active agents include cationic, anionic, or non-ionic surfactants, or combinations thereof.
  • Suitable surfactants include, but are not limited to, behentrimonium chloride, benzalkonium chloride, benzethonium chloride, benzododecinium bromide, carbethopendecinium bromide, cetalkonium chloride, cetrimonium bromide, cetrimonium chloride, cetylpyridine chloride, didecyldimethylammonium chloride, dimethyldioctadecylammonium bromide, dimethyldioctadecylammonium chloride, domiphen - 69 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) bromide, lauryl methyl gluceth-10 hydroxypropyl dimonium chloride, tetramethylammonium hydroxide, thonzonium bromide, stearalkonium chloride, octenidine dihydrochloride, olaflur, N-oleyl-1,3
  • One or more surfactants can each be individually present in the composition in an amount of about 0.01% w/w to about 90% w/w relative to weight of the dosage form.
  • One or more surfactants can each be individually present in the composition in an amount of at least, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w/w relative to weight of the dosage form.
  • Suitable diluents include, but are not limited to, calcium carbonate, magnesium carbonate, magnesium oxide, sodium carbonate, lactose, microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate, and sodium phosphate, Cellactose ® 80 (75 % ⁇ - lactose monohydrate and 25 % cellulose powder), mannitol, pre-gelatinized starch, starch, sucrose, sodium chloride, talc, anhydrous lactose, and granulated lactose.
  • One or more diluents can each be individually present in the composition in an amount of about 0.01% w/w to about 90% w/w relative to weight of the dosage form.
  • One or more diluents can each be individually present in the composition in an amount of at least, greater than, or less than - 70 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w/w relative to weight of the dosage form.
  • Suitable granulating and disintegrating agents include, but are not limited to, sucrose, copovidone, corn starch, microcrystalline cellulose, methyl cellulose, sodium starch glycollate, pregelatinized starch, povidone, sodium carboxy methyl cellulose, sodium alginate, citric acid, croscarmellose sodium, cellulose, carboxymethylcellulose calcium, colloidal silicone dioxide, crosspovidone and alginic acid.
  • One or more granulating or disintegrating agents can each be individually present in the composition in an amount of about 0.01% w/w to about 90% w/w relative to weight of the dosage form.
  • One or more granulating or disintegrating agents can each be individually present in the composition in an amount of at least, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w/w relative to weight of the dosage form.
  • Suitable binding agents include, but are not limited to, gelatin, acacia, pre-gelatinized maize starch, polyvinylpyrrolidone, anhydrous lactose, lactose monohydrate, hydroxypropyl methylcellulose, methylcellulose, povidone, polyacrylamides, sucrose, dextrose, maltose, gelatin, polyethylene glycol.
  • One or more binding agents can each be individually present in the composition in an amount of about 0.01% w/w to about 90% w/w relative to weight of the dosage form.
  • One or more binding agents can each be individually present in the composition in an amount of at least, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w/w relative to weight of the dosage form.
  • Suitable lubricating agents include, but are not limited to, magnesium stearate, calcium stearate, hydrogenated castor oil, glyceryl monostearate, glyceryl behenate, mineral oil, polyethylene glycol, poloxamer 407, poloxamer 188, sodium laureth sulfate, sodium benzoate, stearic acid, sodium stearyl fumarate, silica, and talc.
  • One or more lubricating agents can each be individually present in the composition in an amount of about 0.01% w/w to about 90% w/w relative to weight of the dosage form.
  • One or more lubricating agents can each be individually present in the composition in an amount of at least, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w/w relative to weight of the dosage form.
  • Tablets can be non-coated or they may be coated using known methods to achieve - 71 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) delayed disintegration in the gastrointestinal tract of a subject, thereby providing sustained release and absorption of the active ingredient.
  • a material such as glyceryl monostearate or glyceryl distearate may be used to coat tablets.
  • tablets may be coated using methods described in U.S. Patent Nos.4,256,108; 4,160,452; and 4,265,874 to form osmotically controlled release tablets.
  • Tablets may further comprise a sweetening agent, a flavoring agent, a coloring agent, a preservative, or some combination of these in order to provide for pharmaceutically elegant and palatable preparation. Tablets can also be enterically coated such that the coating begins to dissolve at a certain pH, such as at about pH 5.0 to about pH 7.5, thereby releasing a compound as described herein.
  • the coating can contain, for example, EUDRAGIT ® L, S, FS, and/or E polymers with acidic or alkaline groups to allow release of a compound as described herein in a particular location, including in any desired section(s) of the intestine.
  • the coating can also contain, for example, EUDRAGIT ® RL and/or RS polymers with cationic or neutral groups to allow for time controlled release of a compound as described herein by pH-independent swelling.
  • Parenteral Administration For parenteral administration, the compounds as described herein may be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose and/or continuous infusion.
  • Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing and/or dispersing agents may be used.
  • Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer’s solution and isotonic sodium chloride solution.
  • Sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain - 72 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) alcohol diluent or dispersant, such as such as lauryl, stearyl, or oleyl alcohols, or similar alcohol.
  • Additional dosage forms suitable for use with the compound(s) and compositions described herein include dosage forms as described in U.S. Patents Nos.6,340,475; 6,488,962; 6,451,808; 5,972,389; 5,582,837; and 5,007,790. Additional dosage forms suitable for use with the compound(s) and compositions described herein also include dosage forms as described in U.S. Patent Applications Nos.20030147952; 20030104062; 20030104053; 20030044466; 20030039688; and 20020051820. Additional dosage forms suitable for use with the compound(s) and compositions described herein also include dosage forms as described in PCT Applications Nos.
  • Controlled Release Formulations and Drug Delivery Systems can be, but are not limited to, short-term, rapid-offset, as well as controlled, for example, sustained release, delayed release and pulsatile release formulations.
  • sustained release is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that may, although not necessarily, result in substantially constant blood levels of a drug over an extended time period.
  • the period of time may be as long as a month or more and should be a release which is longer that the same amount of agent administered in bolus form.
  • the compounds may be formulated with a suitable polymer or hydrophobic material which provides sustained release properties to the compounds.
  • the compounds for use with the method(s) described herein may be administered in the form of microparticles, for example, by injection or in the form of wafers or discs by implantation.
  • the dosage forms to be used can be provided as slow or controlled- release of one or more active ingredients therein using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, or microspheres or a combination thereof to provide the desired release profile in varying proportions.
  • Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the pharmaceutical compositions described herein.
  • single unit dosage - 73 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) forms suitable for oral administration, such as tablets, capsules, gelcaps, and caplets, that are adapted for controlled-release are encompassed by the compositions and dosage forms described herein.
  • Most controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts.
  • the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time.
  • Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance.
  • controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood level of the drug, and thus can affect the occurrence of side effects.
  • Most controlled-release formulations are designed to initially release an amount of drug that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body.
  • Controlled-release of an active ingredient can be stimulated by various inducers, for example pH, temperature, enzymes, water, or other physiological conditions or compounds.
  • controlled-release component is defined herein as a compound or compounds, including, but not limited to, polymers, polymer matrices, gels, permeable membranes, liposomes, or microspheres or a combination thereof that facilitates the controlled-release of the active ingredient.
  • the compound(s) described herein are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation.
  • the compound(s) described herein are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation.
  • delayed release is used herein in its conventional sense to refer to a drug formulation that provides for an initial release of the drug after some delay following drug administration and that mat, although not necessarily, includes a delay of from about 10 minutes up to about 12 hours.
  • pulsatile release is used herein in its conventional sense to refer to a drug formulation that provides release of the drug in such a way as to produce pulsed plasma - 74 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) profiles of the drug after drug administration.
  • immediate release is used in its conventional sense to refer to a drug formulation that provides for release of the drug immediately after drug administration.
  • short-term refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes and any or all whole or partial increments thereof after drug administration after drug administration.
  • rapid-offset refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any and all whole or partial increments thereof after drug administration.
  • the therapeutically effective amount or dose of a compound described herein depends on the age, sex and weight of the patient, the current medical condition of the patient and the progression of a disease state in the patient being treated. The skilled artisan is able to determine appropriate dosages depending on these and other factors.
  • a suitable dose of a compound described herein can be in the range of from about 0.01 mg to about 5,000 mg per day, such as from about 0.1 mg to about 1,000 mg, for example, from about 1 mg to about 500 mg, such as about 5 mg to about 250 mg per day.
  • the dose may be administered in a single dosage or in multiple dosages, for example from 1 to 4 or more times per day. When multiple dosages are used, the amount of each dosage may be the same or different.
  • a dose of 1 mg per day may be administered as two 0.5 mg doses, with about a 12-hour interval between doses. It is understood that the amount of compound dosed per day may be administered, in non-limiting examples, every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days. For example, with every other day administration, a 5 mg per day dose may be initiated on Monday with a first subsequent 5 mg per day dose administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday, and so on.
  • the administration of the compound(s) described herein is optionally given continuously; alternatively, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”).
  • the length of the drug holiday optionally varies between 2 days and 1 year, including by way of example only, 2 days, 3 - 75 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days.
  • the dose reduction during a drug holiday includes from 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.
  • a maintenance dose is administered if necessary.
  • the dosage or the frequency of administration, or both is reduced to a level at which the improved disease is retained.
  • patients require intermittent treatment on a long-term basis upon any recurrence of symptoms and/or infection.
  • the compounds described herein can be formulated in unit dosage form.
  • unit dosage form refers to physically discrete units suitable as unitary dosage for patients undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier.
  • the unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose. Toxicity and therapeutic efficacy of such therapeutic regimens are optionally determined in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between the toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LD50 and ED 50 .
  • the data obtained from cell culture assays and animal studies are optionally used in formulating a range of dosage for use in human.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with minimal toxicity.
  • the dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized.
  • the libraries were incubated with MCR-1 and the complexes were captured using Nickel-beads and washed. Bound small molecules were released and bound again to fresh MCR-1 protein for two additional rounds of enrichment.
  • the DNA section of the conjugates was amplified by PCR and subjected to deep sequencing. Bioinformatics analysis was used to reveal the sequences most highly represented after the binding selection as described in Faver, John C., et al. "Quantitative comparison of enrichment from DNA-encoded chemical library selections.” ACS combinatorial science 21.2 (2019): 75-82. Because the barcode DNA sequence encodes the small molecule building blocks added, it reveals the structure of library members that bound the target protein.
  • CDD-2901, CDD-2750, CDD-3002, CDD-2918, CDD- 2902, CDD-3019, and CDD-2847 (FIGs.9-10). All of these compounds showed significant activity by the spot assay (>100x) and, for some, MIC against E. coli XL1-Blue encoding MCR- 1 (FIGs.9-10). Docking CDD-1794 and CDD-1938 to an MCR-1 homology model- The structure of full-length MCR-1 is not known.
  • a homology model was constructed based on the structure of NmEptA, which has 37% sequence identity - 77 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) to MCR-1.
  • Autodock Vina was used to computationally dock CDD-1794 and CDD-1938 to the MCR-1 homology model (FIGs.8A-8B).
  • the highest ranked pose of each compound is bound in a similar pocket near the catalytic Thr285 residue.
  • the compounds are predicted to bind in a similar position as where dodecyl- ⁇ -D-maltoside was found in the NmEptA structure and was proposed as the phosphatidylethanolamine binding site.
  • CDD compounds for cytotoxicity versus human cells. An important question is whether the compounds that have activity against strains expressing MCR-1 are cytotoxic to human cells. This was addressed in cytotoxicity testing using human HepG2 cells. A set of potent compounds including CDD-2750, CDD-2901, CDD-2847, and CDD-2902 was tested. A HepG2 cell line was used to screen for in vitro metabolism-associated drug toxicity using cell viability assays that measure the number of live cells after a 24-hour incubation with increasing concentrations (0-100 ⁇ M) of compounds. A CellTiter-Glo ⁇ Luminescent Cell Viability Assay was used to determine the number of viable cells in culture. Bacterial strains and expression vectors E.
  • MCR-1-StrepII Strep-tag II-fused MCR-1
  • Pfu polymerase Invitrogen
  • MCR-1-StrepII-pTP470 an isopropyl- ⁇ -d-thiogalactopyranoside (IPTG)-inducible trc promoter
  • Strep-tag II at the C-terminus of MCR-1 was used to monitor the expression of MCR-1 in E. coli by immunoblotting with anti-Strep tag II antibody, it was not used in this study.
  • the Strep tag II-modified MCR-1 plasmid construct was shown to provide colistin resistance to E. coli XL1-Blue cells.
  • mcr-1 was cloned between NdeI and XhoI restriction sites of a modified pET28a vector (Novogen), in which the thrombin recognition sequence was replaced with the tobacco etch virus (TEV) protease recognition sequence and 2 extra codons for histidine residues were inserted before the TEV protease recognition sequence to increase binding affinity of His-tagged target proteins to the HisTrap - 78 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) columns.
  • TEV tobacco etch virus
  • the clinical isolates (independently determined to have plasmid-encoded antibiotic resistance genes and microdilution MICs based on CLSI testing standards where the resistance cut-off is 4 ⁇ g/mL) were obtained from the Center for Disease Control & Prevention (CDC)/US Food & Drug Administration (FDA) Antibiotic Resistance (AR) Isolate Bank panel entitled “Isolates with new or novel antibiotic resistance (NEW)”.
  • the strains in the panel are as follows: K.
  • coli cells containing the MCR-1 expression plasmid were grown at 37°C to an OD600 of 0.8 in LB medium containing 25 ⁇ g/ml kanamycin. Expression of the His-MCR-1 protein was induced with 0.5 mM IPTG at 18°C for 16 h.
  • the cells were pelleted and suspended in lysis buffer (20 mM HEPES, 150 mM NaCl, pH 7.4) and lysed using a French press and a short period of sonication. The cell debris was removed by centrifugation at 12,000 ⁇ g for 30 min, and the membranes were isolated by ultracentrifugation at 170,000xg for 1.5 hours at 4°C.
  • His-MCR-1 was solubilized from the membranes by incubating the isolated membranes at 4°C overnight with gentle shaking with 20 mM n-dodecyl- ⁇ -d-maltopyranoside (DDM) in 20 mM HEPES, pH 7.4, 300 mM NaCl, 1 ⁇ EDTA-free protease inhibitor cocktail (Gendepot).
  • DDM n-dodecyl- ⁇ -d-maltopyranoside
  • HEPES pH 7.4
  • 300 mM NaCl 1 ⁇ EDTA-free protease inhibitor cocktail
  • Solubilized His-MCR-1 was purified by metal-chelating chromatography by loading the supernatant from the ultracentrifugation onto a 1-mL HisTrap FF column (GE - 79 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) Healthcare), which had been equilibrated by Buffer A (20 mM HEPES, pH 7.4, 300 mM NaCl, 20 mM imidazole, 0.5 mM DDM, 1 mM phenylmethylsulfonyl fluoride [PMSF]).
  • Buffer A (20 mM HEPES, pH 7.4, 300 mM NaCl, 20 mM imidazole, 0.5 mM DDM, 1 mM phenylmethylsulfonyl fluoride [PMSF]).
  • Buffer A After washing with 5 column volumes (CVs) of Buffer A, the bound proteins were eluted with 0 to 100% Buffer B (20 mM HEPES, pH 7.4, 300 mM NaCl, 500 mM imidazole, 0.5 mM DDM, 1 mM PMSF) over 10 CVs. Fractions containing His-MCR-1 were pooled, concentrated, and buffer exchanged to Buffer A with a 50-kDa cut-off Amicon Ultra-15 centrifugal filter unit (EMD Millipore).
  • Buffer B 20 mM HEPES, pH 7.4, 300 mM NaCl, 500 mM imidazole, 0.5 mM DDM, 1 mM PMSF
  • the His-tag was cleaved by incubating with TEV protease for 16 hours at 4°C at a ratio of 1:50, and the TEV protease was removed by incubating with Ni-Sepharose 6 fast-flow resin (GE Healthcare).
  • MCR-1 was further purified by gel filtration chromatography using a Superdex 200 Increase GL 10/300 sizing column (GE Healthcare) with 20 mM HEPES, pH 7.4, 150 mM NaCl, 0.5 mM DDM, 1 mM PMSF as running buffer. Fractions containing MCR-1 were pooled and concentrated.
  • the DNA-encoded chemical library (DECL) was mixed with 1 or 5 ⁇ M of His-MCR- 1 in 200 ⁇ L of selection buffer ([20 mM HEPES pH 7.5, 134 mM potassium acetate, 10 mM imidazole, 1 mM TCEP, 8 mM sodium acetate, 0.8 mM magnesium acetate, 1 mM CHAPS, 4 mM sodium chloride, and 0.1 mg/mL Sheared Salmon Sperm DNA]).
  • selection buffer [20 mM HEPES pH 7.5, 134 mM potassium acetate, 10 mM imidazole, 1 mM TCEP, 8 mM sodium acetate, 0.8 mM magnesium acetate, 1 mM CHAPS, 4 mM sodium chloride, and 0.1 mg/mL Sheared Salmon Sperm DNA]
  • NTC non-target control
  • sterile Luria Bertani (LB) Becton Dickinson agar plates supplemented with 12.5 ⁇ g/mL chloramphenicol (for plasmid maintenance) were prepared containing: 1) subinhibitory concentration (0.32 ⁇ g/mL) of colistin sodium methane sulfonate (CMS) antibiotic only (adjusted for colistin base using an adjustment factor of 2.56X in water); 2) high inhibitor compound concentration (12.5 ⁇ M) only and 3) no antibiotic/inhibitor, and test plates containing: 4) low inhibitor concentration (3.25 ⁇ M) and CMS antibiotic (0.32 ⁇ g/mL); 5) medium inhibitor concentration (6.25 ⁇ M) and CMS antibiotic (0.32 ⁇ g/mL), and 6) high inhibitor concentration (12.5 ⁇ M) and CMS antibiotic (0.32 ⁇ g/mL).
  • CMS colistin sodium methane sulfonate
  • Dilutions were transferred to a 96 well plate and a multichannel pipette was used to transfer 7 ⁇ L of dilutions, prepared as biological triplicates, onto each of the control and test plates. Spots were allowed to dry by absorption, and plates were inverted and incubated at 37oC overnight. Plates, without the lid, were photographed and growth was visually confirmed. Viability was our endpoint. Growth on the test plates was compared to growth on the control plates. Growth was defined as the presence of single colonies or overall growth coverage within the spot. Clinical isolates were sub-cultured from -80oC freezer stocks onto 5% sheep blood agar plates and spot assays were prepared the same as the laboratory strains.
  • the colistin MIC was defined as the lowest concentration of colistin ⁇ inhibitor that inhibited visible growth of bacterial culture after overnight incubation. No inoculum controls were included.
  • Time-kill curve assays Initially, growth curves were carried out to confirm that strains would reach a stable early to mid-log phase by 4-5 hours and inoculum was adjusted accordingly.
  • Time-kill curve (TKC) assays were performed in a 96-well format with a final volume of 100 ⁇ L per well. Briefly, E.
  • Thin-layer chromatography was performed on silica gel 60 F254 plates (E. Merck). Non-UV active compounds were visualized on thin-layer chromatography (TLC) using one of the following stains: KMnO 4 , ninhydrin, p-anisaldehyde, 2,4-DNP, or bromocresol green.
  • TLC thin-layer chromatography
  • Liquid chromatography-mass spectrometry (LC-MS) used for data collection was a 1290 Infinity Series liquid chromatography with a 6150 mass spectrometer system (Agilent).
  • the solid phase column was an Agilent Eclipse Plus C18, 2.1 mm ⁇ 50 mm (8 ⁇ m), and the mobile phase solvents were A: 0.05% formic acid in water and B: 5% water in acetonitrile. Peak detection was done at 254 and 230 nm.
  • the high-resolution mass spectrometry (HRMS) data were acquired on a Thermo Q Exactive Orbitrap MS coupled with a Thermo Vanish UHPLC.
  • the Zorbax XDB-C18 (4.6 mm ⁇ 50 mm, 3 ⁇ m) was used for separation and kept at 40 °C.
  • the flow rate used was 0.3 mL/min with a gradient ranging from 2 to 95% aqueous acetonitrile containing 0.1% formic acid in a 7 min run.
  • Q Exactive MS was operated in - 83 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) positive mode with electrospray ionization.
  • the lock mass at m/z 371.1012 for positive mode was used as a reference ion during acquisition. All compounds are >95% pure by HPLC.
  • NMR spectra were collected using a Bruker 600 or 151 MHz NMR for 1 H and 13 C, respectively. All NMR chemical shifts were referenced to the residual nondeuterated solvent as an internal standard.
  • the procedure involves adding the CellTiter-Glo ⁇ reagent to the cells whereby it lyses the cell membranes to release ATP, the reagent inhibits endogenous ATPases and provides luciferin and luciferase needed to measure ATP using a bioluminescent reaction.
  • a CLARIOstar plate reader was used to detect the signal and measure the ATP in viable cells.
  • the CellTiter-Blue ⁇ Cell Viability Assay which uses an optimized reagent containing resazurin that can enter living cells where it is reduced to the fluorescent resorufin product; this conversion is proportional to the number of metabolically active, viable cells present in a culture.
  • the HepG2 cells in the assay plate are incubated at 37°C for 24 hours. The signal is measured using a standard multi-well fluorometer.
  • % viability is plotted as a function of compound concentration (uM), and non-linear regression (Log(concentration)-normalized cell viability) is used to calculate the half-maximal inhibitory concentration (IC 50 ) with Prism 10.0.
  • IC 50 cut-off values compounds retaining 100X antimicrobial activity at a concentration equal to 10% of the IC50 were considered to have a low cytotoxicity profile.
  • Example 1 DNA encoded library (DECL) screening for MCR-1 inhibitors
  • DECL DNA-encoded chemical library technology
  • An innovative aspect of the present disclosure is the use of DNA-encoded chemical library technology (DECL) to explore chemical space to identify small molecule high affinity - 84 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) binders for the clinically important MCR-1 mobile colistin resistance enzyme for discovery of novel inhibitors.
  • the DECL approach involves the creation of libraries of drug-like molecules covalently attached to a unique DNA barcode that enables identification of binders for a target in a pool of millions of compounds (FIG.3).
  • the conjugates are constructed in sequential cycles of chemical attachment of drug-like fragments (chemical building blocks) to a molecular scaffold concomitantly encoded through the ligation of a unique DNA barcode.
  • the libraries can be screened against a tagged version of the protein target to identity molecules with high affinity, which are isolated though the pull-down of the tag from solution.
  • Next-generation DNA sequencing allows the determination of the DNA barcode sequences isolated and, thus, the structures of the high-affinity compounds.
  • the DECL approach was applied to identify small molecule inhibitors of the OXA-48 carbapenemase, NDM-1 metallo- ⁇ -lactamase, and SARS CoV-2 Mpro protease.
  • the present example applies a similar strategy to identify inhibitors of MCR-1.
  • Example 2 Crystal structure of the catalytic domain of MCR-1
  • the MCR-1 protein is predicted to consist of a membrane-spanning domain and a periplasmic catalytic domain.
  • the X-ray crystal of the catalytic domain (cMCR) was determined at 1.32 ⁇ resolution.
  • cMCR-1 is a zinc metallo-enzyme that assumes a ⁇ / ⁇ / ⁇ fold characteristic of the alkaline phosphatase superfamily.
  • an active-site zinc in an analogous position as the catalytic zinc in alkaline phosphatase may stabilize the alkoxide form of Thr285 for nucleophilic attack on the phosphate of the phosphatidylethanolamine substrate to create an intermediate with Thr285 linked to PEA.
  • Binding of lipid A in an appropriate position for nucleophilic attack on the lipid A 1’ or 4’ phosphate on the phosphate of the Thr285-PEA intermediate could then transfer the group to lipid A.
  • Example 3 MCR-1 expression reduces E. coli susceptibility to polymyxins - 85 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) If Thr285 is the catalytic nucleophile, mutation of this residue would be expected to greatly decrease MCR-1 function. This was tested by mutating this residue to alanine in a plasmid encoding the full-length mcr-1 gene and measuring the minimum inhibitory concentration (MIC) of colistin and polymyxin B.
  • MIC minimum inhibitory concentration
  • the protein was expressed in E. coli and a cell lysate was solubilized using 30 mM dodecyl- ⁇ -D- maltoside (DDM) detergent, centrifuged, and the supernatant was filtered and subjected to affinity purification using a nickel-sepharose resin.
  • DDM dodecyl- ⁇ -D- maltoside
  • the His-tag was removed by with TEV protease and separated from MCR-1 on a nickel-charged resin.
  • the MCR-1 protein was then further purified by size exclusion chromatography.
  • CDD-1938 The DNA is attached via a linker to the C1 position while the C2 position branches from C1 and C3 branches from the C2 position.
  • the CDD-1938 compound that was synthesized off-DNA and shows activity against E. coli expressing MCR-1 contains C1, C2, and C3 substituents.
  • CDD-1938 is a racemic mixture with a chiral center at the phenyl substitution on the piperazine ring on C1. Both enantiomers of CDD-2778 (R-enantiomer) grew up to a 100-fold lower dilution than the colistin only control, which reflects a 10-fold increase in potency compared to CDD-1938, while E.
  • CDD-2932 shows a 100-fold loss in potency in the spot assay compared to the CDD-2750 parent compound, indicating the C3 group makes important contributions to binding.
  • CDD-2889 which retains the C3 phenyl but is lacking the isopropyl group also showed a 100-fold decrease in potency relative to the CDD-2750 parent, revealing the importance of the isopropyl group for inhibition.
  • the original CDD-1938 hit compound and the more potent CDD-2750 analog contain a halide (Cl) appended to the phenyl group at the C1 position.
  • CDD-2835 is CDD-2750 lacking the halide. This compound showed a 100-fold loss in potency relative to CDD-2750, indicating the importance of the halide for potency.
  • the Cl in CDD-2750 was replaced with fluorine (F) to create CDD-3228, which displayed similar potency in the spot assay as CDD- 2750.
  • the Cl was also replaced by F in CDD-2901, which has a benzyl rather than a pyridine ring at C2, to create CDD-3002.
  • CDD-3002 showed similar potency as CDD-2901 in the spot assay.
  • both of the F-containing compounds exhibited similar potency as the parent compounds while the lack of a halide decreased potency, indicating the importance of Cl or F at this position.
  • the C3 moiety is critical for inhibition and the isopropyl group appended to the phenyl at C3 is important.
  • Different substituents were also examined on the C3 phenyl group. Notably, the addition of a hydroxyl at the 2 position and a trifluoromethoxy group at the 5 position of the phenyl ring enhanced potency.
  • the CDD-2847 and CDD-2902 compounds containing these changes exhibited a 10-fold increase in potency compared to the parent compounds CDD-2750 and CDD-2901. E.
  • CDD-2847 and CDD-2902 are the most potent antibacterial compounds identified in the SAR studies herein. - 88 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) As described above, all of the analog compounds were tested against E. coli expressing MCR-1 using the spot test shown in FIG.7.
  • MICs minimum inhibitory concentrations
  • the colistin MIC in the absence of compounds is 4.0 ⁇ g/ml in all experiments (FIG.10).
  • the colistin MIC is 2 ⁇ g/ml at 6.25 ⁇ M CDD-1938, 1 ⁇ g/ml at 50 ⁇ M, and 0.5 ⁇ g/ml at 100 ⁇ M compound.
  • CDD-2750 which is 10-fold more potent than CDD-1938 in the spot assay
  • the colistin MIC is 0.125 ⁇ g/ml at 6.25 ⁇ M compound and 0.0156 ⁇ g/ml at 50 ⁇ M compound.
  • the colistin MIC is 0.0156 ⁇ g/ml at 6.25 ⁇ M compound and 0 ⁇ g/ml at 25 ⁇ M compound.
  • CDD-2901 has similar MIC values as CDD- 2847 (FIG.10).
  • CDD-2847 and CDD-2901 are very potent compounds as measured by MIC.
  • CDD- 2847 As seen in FIG.11, the most potent compound against the clinical strains is CDD- 2847, which also displayed high potency by spot and MIC versus the laboratory strain of E. coli.
  • CDD-2847 showed a 10000-fold effect compared to the colistin only control for all of the E. coli MCR-1 clinical strains but showed a 10-fold effect versus the K. pneumoniae strain.
  • CDD-3019, CDD-2902, and CDD-2918 also showed 100-1000x activity against the E. coli strains and 10x activity versus K. pneumoniae.
  • CDD-3002, CDD-2750, and CDD-2901 showed progressively less activity towards E. coli and no activity against the K. pneumoniae strain.
  • CDD-3083 is CDD-2901 with a piperidine ring replacing the pyrazine ring. The spot test, however, showed CDD-3083 has no activity.
  • CDD-3124 is CDD-2901 with a pyrrolidine ring replacing the pyrazine but it also shows no activity in the spot test. Compounds with various substituents on the nitrogen of the pyrazine ring were examined.
  • CDD-3259 is CDD- 2901 with a pyridine ring attached to the pyrazine nitrogen. The spot test revealed CDD-3259 retains activity but is 100-fold less potent compared to CDD-2901.
  • CDD-3295 is CDD-2901 with a guanidinium group at the pyrazine nitrogen. Interestingly, the spot test showed this compound is only 10-fold less potent than CDD-2901 and thus shows 100x activity compared to the colistin only control.
  • Exemplary colistin sulfate minimum inhibitory concentration (MIC) data Cmpd Colistin sulfate MIC ( ⁇ g/mL) - 90 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) concentration E. coli XL1Blue + K. pneumoniae AR E.
  • MIC minimum inhibitory concentration
  • pneumoniae used LB media, and for E. coli it used LB+ chloramphenicol (12.5 ⁇ g/mL) to maintain the plasmid carrying the wild type mcr-1 or T285A mcr-1 mutant gene.
  • the 96-well culture plates were grown for 20.5 hrs at 35°C with 200 revolutions per minute (RPM) orbital shaking.
  • NA Not available
  • ND Not determined
  • ( ) unclear if there was growth, difficult to read; data obtained using microdilution method.
  • Table 6 Exemplary colistin sulfate minimum inhibitory concentration (MIC) data Colistin sulfate MIC ( ⁇ g/mL) Compound E. coli XL1Blue + WT MCR-1 E.
  • Example 6 Testing of certain exemplary compounds for cytotoxicity versus human cells Based on the cytotoxicity results, a structure-activity study was performed to reduce the toxicity of antibiotic compounds. It was hypothesized that the basicity of the secondary - 91 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) amine on the pyrazine ring may contribute to toxicity and therefore synthesized a series of morpholines with oxygen replacing the nitrogen. Table 7 summarizes the HepG2 cellular assay results.
  • Compound CDD-3212 is a morpholine derivative of CDD-2902.
  • CDD-3213 and CDD-3239 are morpholine derivatives of CDD-2901 and CDD-3002 and the spot assay shows a >100-fold decrease in potency.
  • CDD-3240 and CDD-3084 are morpholine derivatives of CDD-3019 and CDD-2901 but also lacking the halide. Spot assay results showed both of these compounds exhibit a >100-fold decrease in potency. Cytotoxicity assays of CDD-3084 with HepG2 cells showed low toxicity with an IC 50 > 100 ⁇ M, suggesting the morpholine modification reduces cytotoxicity.
  • the spot assay indicated that, although it is less potent than CDD-2901, it has 10-100X activity compared to the colistin only control.
  • the IC50 for HepG2 cells is >100 ⁇ M, suggesting this is a candidate for further study.
  • CDD-3003 is the methylated version CDD-3002 and the spot assay revealed it has 100x activity compared to the colistin control.
  • the IC 50 for HepG2 cells is 51 ⁇ M, indicating relatively low toxicity.
  • CDD-3337 is the methylated version of CDD-3228 and the spot assay showed it has 100x activity compared to the colistin control. Interestingly, it has similar activity as the parent CDD-3228.
  • CDD-3350 is the methylated version of CDD-3227, which displayed 100x activity compared to the colistin control in the spot assay. CDD-3350 also showed 100x activity relative to the colistin control. However, the IC 50 of CDD-3350 for HepG2 cells is 28 ⁇ M, indicating moderate toxicity. Based on potency and toxicity, CDD-3003 and CDD-3737 are the top candidates for advancement from the CDD-1938 series. In addition, cytotoxicity assays with human HepG2 cells showed only modest toxicity for CDD-3356 with an IC50 of 53 ⁇ M.
  • coli MCR-1 plays a central role in lipid A modification in E. coli and confers colistin resistance.
  • WT wild type
  • T285A MCR-1 a catalytically inactive mutant expressed from a plasmid were grown in rich media with and without colistin antibiotic over 6 hours up to 24 hours. It was shown that WT MCR-1 de-sensitizes E. coli to various concentrations of colistin, while the lack of a catalytically functional MCR-1 results in the sensitization of E. coli to colistin (FIG. 14 and FIG.22). WT and mutant strains grew similarly without antibiotics (FIG.14).
  • DNA-encoded chemical libraries consisting of a total of 2 billion compounds were screened against purified N-terminal 6xHis-tagged full-length E. coli WT MCR-1.
  • DNA-encoded small molecule/protein complexes were captured using nickel beads - 93 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) and washed. Bound small molecules were released and bound again to fresh MCR-1 protein for two additional rounds of enrichment. After the final elution, the DNA section of the conjugates was amplified by PCR and subjected to deep sequencing. Bioinformatics analysis was used to identify the sequences most highly represented after the binding selection.
  • the spot assay results showed CDD-1938 and CDD-1794 reduced the growth of E. coli/MCR-1 in combination with colistin (FIG.16A).
  • the presence of increasing concentrations of CDD-1938 resulted in progressively greater susceptibility of E. coli/MCR-1; however, a dose-dependent susceptibility was not observed for the concentrations of CDD-1794 tested.
  • the viability of E. coli/MCR-1 and E. coli/T285A on control and test plates was evaluated. For example, on the plates containing the highest inhibitor concentration (12.5 ⁇ M) and 0.32 ⁇ g/mL colistin, E.
  • coli/MCR-1 grew to a 10-fold lower dilution compared to growth on plates containing 0.32 ⁇ g/mL colistin with no inhibitor (FIG.16A). This difference in growth between treatments was scored as a 10X effect for the inhibitors CDD-1938 or CDD-1794, which showed similar results. It was confirmed that MCR-1 was the target of the compounds by testing against E. coli with the catalytically inactive MCR-1 T285A mutant, where the expression of the mutant MCR-1 fails to protect E. coli from colistin. Unlike with E. coli/MCR-1, no effect of the compounds was observed in combination with colistin against E.
  • Example 10 Optimization and prioritization of certain exemplary chemotype I MCR-1 inhibitors The development of compounds that inhibit MCR-1 and show bioactivity in the 1 ⁇ g/mL range in the colistin MIC assay were sought. These potencies would compare favorably with the potencies observed for beta-lactamase inhibitors in clinical use.
  • both chemotype CDD-1938 and CDD-1794 were synthesized and tested for bioactivity as described above.
  • the SAR approach focused on modifying and testing the DECL cycle building blocks for each compound; in this case, both chemotype CDD-1938 and CDD-1794 consisted of three cycle building blocks (BB) each, which were designated as C1 BB, C2 BB and C3 BB (FIGs.15A-15B).
  • Compound CDD-1938 is a racemic mixture with a chiral center at the phenyl substitution on the piperazine ring on the C1 BB (FIG.15A). Both enantiomers were synthesized and tested for activity.
  • CDD-1938 and its more potent analog, CDD-2750 contain a halide appended to the phenyl group at the C1 BB (FIG.15A and FIG.15C).
  • CDD-2835 is CDD-2750 lacking the halide (FIG.26). This compound showed a 100-fold loss in potency relative to CDD-2750, revealing the importance of the halide for inhibitor bioactivity.
  • the chlorine in CDD-2750 was also replaced with fluorine to create CDD-3228, which exhibited similar potency in the spot assay as CDD-2750 (FIG.26).
  • the absence of the linker improved the potency of the inhibitor, and the stereochemistry of the chiral carbon of the piperazine ring did not noticeably impact inhibitor potency.
  • CDD-2901 The pyridine ring in CDD-2750 was replaced with a benzyl ring to create CDD-2901 (FIG.15C) and the spot assay showed no change in potency against E. coli/MCR-1, suggesting the nitrogen was not important for inhibition (FIG.17).
  • the Cl was substituted by an F in CDD-2901, which possesses a benzyl rather than a pyridine ring at C2, to create CDD-3002 (FIG.17C).
  • CDD-3002 displayed similar potency to CDD-2901 based on the spot assay (FIG.17).
  • CDD-2847 and CDD-2902 are the most potent compounds that were identified in the SAR studies for chemotype CDD-1938.
  • Example 11 Activity of certain exemplary chemotype 1 MCR-1 inhibitors against colistin resistant clinical isolates
  • the spot assay was next used to examine the activity of a subset of compounds against a set of five clinically relevant isolates that were obtained from the CDC & FDA Antibiotic Resistance Isolate Bank. These isolates include MDR strains that are validated for - 97 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) the presence of the MCR-1 or MCR-2 colistin resistance genes.
  • the MCR-2 variant shares 81% amino acid identity with MCR-1.
  • coli strains were tested using spot assays with 0.32 ⁇ g/mL CMS and 12.5 ⁇ M compound (FIG.19).
  • a total of seven chemotype 1 compounds were evaluated including CDD-2901, CDD-2750, CDD-3002, CDD-2918, CDD-2902, CDD-3019 and CDD-2847. All of these compounds had been shown to have significant activity in the spot assay ( ⁇ 100X) (FIG.17 and FIG.26) and, for some, by MIC against E. coli/MCR-1 (FIGs.18A-18B).
  • the most potent compound against clinical strains is CDD-2847, which also displayed the highest potency by spot and MIC versus the E. coli/MCR-1 laboratory strain.
  • CDD-2847 showed a 10,000-fold effect compared to the colistin only control for all the E. coli/MCR-1 clinical strains; however, it exhibited a 10-fold effect against the K. pneumoniae strain. Without wishing to be bound by any theory, this may be due to its difficult-to-permeate capsule and the presence of efflux pumps such as the OqxA pump.
  • the low sub-inhibitory concentration of colistin at 0.32 ⁇ g/mL, in combination with the inhibitor, may also affect its efficacy in killing K. pneumoniae. It is hypothesized that killing will be more effective when colistin concentration is increased.
  • CDD-3019, CDD-2902 and CDD-2918 also showed >1000-fold activity against all five of the E.
  • CDD-3002, CDD-2750 and CDD-2901 displayed progressively less activity towards E. coli and no activity against the K. pneumoniae strain.
  • these three latter compounds have an isopropyl on the C3 BB compared to the C3 BB on the former three compounds, which possess the -OH and -OCF3 combination.
  • these compounds displayed potent activity against E. coli clinically relevant strains, but to a lesser degree against K. pneumoniae clinical isolates.
  • CDD-2750, in combination with colistin was tested, as described above, against seven E.
  • Example 12 Cytotoxicity profile of certain exemplary chemotype 1 MCR-1 inhibitors The potential for cytotoxicity was examined by testing a set of potent compounds including CDD-2750, CDD-2901, CDD-2847 and CDD-2902 against the human HepG2 cell line. The viability assays revealed that the compounds show significant cytotoxicity against the HepG2 cells with IC 50 values ranging from 14-21 ⁇ M (Table 8).
  • Cytotoxicity of enhanced potency MCR-1 inhibitors measured against human and mouse hepatocytes IC 50 ( ⁇ M) Compound Primary human Primary mouse HepG2 hepatocytes hepatocytes hepatocytes CDD-2750 21.41 8.63 ⁇ 10 CDD-2901 15.85 ND ⁇ 10 CDD-2847 15.63 9.81 ⁇ 10 CDD-2902 14.02 ND ⁇ 10 Compounds were incubated at different concentrations (0-100 ⁇ M) with human HepG2 and primary human hepatocytes and incubated at room temperature for 24 hours. Viability of cells was determined using the CellTiterGlo assay. Primary human hepatocytes (PHH) were cryopreserved, 100-donor mixed gender.
  • Example 13 Structure-activity studies to reduce toxicity and maintain potency Based on the results described elsewhere herein, additional structure-activity studies were performed to reduce the cytotoxicity of the compounds. It was hypothesized that the basicity of the secondary amine on the piperazine ring contributes to the toxicity and therefore a series of morpholines were synthesized with oxygen replacing the nitrogen at position 1 (FIG.26). Compound CDD-3212 is a morpholine derivative of CDD-2902 (FIG. 26).
  • CDD-3213 and CDD-3239 are morpholine analogs of CDD-2901 and CDD-3002 (FIG.26) and the spot assay revealed a >100-fold reduction in potency (FIG.26).
  • compound CDD-3240 a morpholine derivative of CDD-2902 with the exception that the - OH and -OCF3 substituents are flipped in position on the C3 BB and the chlorine is substituted for a F on the C1 BB
  • CDD-3084 Cytotoxicity assays of CDD-3084 with HepG2 cells showed low toxicity with an IC50 > 100 ⁇ M, indicating the morpholine modification reduces cytotoxicity (FIG.26); however, potency was lost and thus, the morpholine analogs were eliminated as candidates. Other modifications on the C1 BB were also assessed.
  • CDD-3083 is CDD-2901 with a piperidine ring replacing the piperazine ring (FIG.26). The spot test results showed the ring substitution in CDD-3083 led to loss of potency, suggesting the substitution of the nitrogen at the 1 position with a carbon is not well tolerated with respect to inhibitor potency, like the oxygen in the morpholine analogs.
  • CDD-3124 is CDD-2901 with a pyrrolidine ring in place of the piperazine, and it showed no activity in the spot test (FIG.26), indicating the presence of a nitrogen in this N1 position is important for activity. Compounds with various substituents on the nitrogen at position 1 of the piperazine ring were also evaluated.
  • CDD-3259 is CDD-2901 with a pyridine ring attached to the piperazine nitrogen (FIG.26). The spot assay showed CDD-3259 retains some activity but is 100-fold less potent compared to CDD-2901.
  • CDD-3295 is CDD-2901 with a guanidine group at the piperazine N1 (FIG.26).
  • CDD-3260 is CDD-3002 with the fluorobenzene ring at the 2-position of the piperazine ring rather than the 1-position (FIG.26). This substitution caused a >10 reduction in activity and was toxic based on the IC 50 of 19 ⁇ M for HepG2 cells, supporting the idea that the basicity of a free piperazine secondary amine contributes to toxicity.
  • CDD-3035 is 10- to 100-fold more active than the colistin-only control, but it was 10-fold less active than its parent compound.
  • the IC50 of CDD-3035 for HepG2 cells was >100 ⁇ M, indicating that methylation of the piperazine N1 greatly reduces cytotoxicity.
  • CDD-3003 (FIG.15C) is the methylated version of CDD-3002 (FIG.15C) and the spot assay showed it has 100-fold activity compared to the colistin-only control (FIG.17)
  • the IC50 for CDD-3003 for HepG2 cells is 64 ⁇ M, indicating relatively low toxicity.
  • CDD-3337 (FIG.26) is the methylated version of CDD-3228 (FIG.
  • CDD-3350 (FIG.26) is CDD-3337 with -OH and -OCF3 instead of isopropyl on C3 BB, which displayed 1000-fold activity relative to the colistin-only control in the spot assay.
  • the IC 50 of CDD-3350 for HepG2 cells is 28 ⁇ M, pointing to moderate toxicity and suggesting the -OH and -OCF3 on the C3 BB play a role in toxicity.
  • CDD-3003 was selected as the lead candidate for the chemotype CDD-1938 series.
  • Example 14 Optimization and prioritization of MCR-1 chemotype 2 lead inhibitors
  • the original DECL hit for CDD-3358 contained a DNA molecule attached via a linker to the C1 BB.
  • the C2 and C3 substituents branch from the C1 BB.
  • CDD-1794 which lacks the DNA linker, ethyl cyclopentane of the C2 group and halide appended to the C3 phenyl group. Focus was placed on modification of CDD-1794, which in combination with colistin exhibits activity against E. coli/MCR-1 in the spot and MIC assays (FIGs.16A-16B).
  • CDD-3359 was synthesized to examine the effect of the addition of an ethyl indole to the C1 BB.
  • E. coli/MCR-1 grew to a 10-fold lower dilution on plates containing colistin with 12.5 ⁇ M of CDD-3359 compared to the colistin-only control, indicating that this addition results in no change to potency compared to CDD-2832 or CDD-1794 (FIG.27).
  • a different addition a chiral ethylnaphthalene at the C1 BB of CDD-2832 to create CDD-3367.
  • CDD-3357 was synthesized by attaching an ethyl methyl trifluoromethyl benzene ring to the C1 BB in the R-configuration. CDD-3357 showed a similar potency to CDD-3367 (FIG.27). It is unclear if this result indicates that stereochemistry at the chiral center of the two substituents does not matter or if it is the result of the size and nature of the substituents.
  • CDD-3356 (FIG.15D), which is an S- enantiomer with a chiral center at the CH2 of the benzyl substituent on the C1 BB.
  • this addition increased the potency of the inhibitor by 10-fold compared to CDD-2833 (FIG. 27) or any of the other inhibitors tested, suggesting the addition of cyclopropane enhances potency in conjunction with the benzyl ring.
  • This expanded chemical space at the C2 BB may increase the permeability characteristics of the inhibitor or improve binding to MCR-1.
  • CDD-3356 cytotoxicity assays with human HepG2 cells displayed only modest toxicity for CDD-3356 with an IC 50 of 53 ⁇ M versus 44 ⁇ M for CDD-3366, and it is difficult to synthesize the S- and R-enantiomers of CDD-3366.
  • the Cl in CDD-3356 was replaced with an F to create CDD-3682, which exhibited a slight decrease in potency in the spot assay compared to CDD-3356, indicating that Cl exhibits improved activity at the 4-position of the C3 phenyl ring.
  • CDD-3356 is a lead candidate for the CDD-1794-related (chemotype 2) series.
  • Example 15 Activity of certain exemplary lead MCR-1 inhibitors against colistin resistant Klebsiella pneumoniae The MIC assay was used to examine the activity of CDD-3356 and CDD-3003 (Table 9) versus a colistin resistant clinical strain of Klebsiella pneumoniae known to contain mcr-1 and a laboratory strain of E. coli expressing WT MCR-1 or catalytically inactive T285A MCR-1.
  • MIC assays were performed by broth microdilution with 2-fold dilutions of colistin sulfate antibiotic and 0, 6.25, 12.5 and 25 ⁇ M compound.
  • the colistin MIC for mcr-1 + K. pneumoniae was 8 ⁇ g/mL.
  • the colistin MIC was reduced by 16-fold to 0.5 ⁇ g/mL (Table 9), indicating that the inhibitor blocks the colistin resistance mechanism encoded by mcr-1.
  • CDD-3003 was also able to reduce the colistin MIC, but less so with an 8-fold reduction at 12.5 ⁇ M (Table 9).
  • CDD-3356 Based on the MIC data, CDD-3356 displays progressively more activity against K. pneumoniae mcr-1 + as its concentration increases when combined with colistin. For colistin/CDD-3003, an abrupt change in colistin MIC occurs at 12.5 ⁇ M, but not at lower inhibitor concentrations. Four-fold less CDD-3356 is needed to re-sensitize K. pneumoniae mcr-1 + at an equivalent level compared to CDD-3003 suggesting CDD-3356 is the more potent inhibitor against this isolate. K.
  • Optimized inhibitors resensitize a Klebsiella pneumoniae clinical isolate and laboratory E. coli carrying wildtype MCR-1 in a dose-dependent manner to colistin killing Colistin sulfate MIC ( ⁇ g/mL) Cmpd K. pneumoniae AR E. coli XL1Blue + WT E.
  • bacterial - 104 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) growth ends at 4 hours, while killing occurs at 5 hours post-treatment with 4 ug/mL colistin and 3.125 or 1.56 ⁇ M CDD-3003 (FIG.20A).
  • Complete killing of E. coli/MCR-1 with the combination treatment occurs by 1.5 hours for CDD-3356 when using 12.5 ⁇ M of the compound, which is at least 2.5 hours before killing occurs with colistin alone.
  • Colistin with CDD-3356 concentrations of 1.56 ⁇ M through 6.25 ⁇ M show varying inhibitory effects with killing between 3 and 4 hours (FIG.20B).
  • the TKC data support that CDD-3003 and CDD- 3356 achieve a similar killing endpoint for E. coli/MCR-1 as seen in the spot assay (FIG.17).
  • a similar response was observed in the colistin MIC results for the K. pneumoniae mcr-1+ strain in the presence of CDD-3003 or CDD-3356 (Table 9).
  • Embodiment 2 provides the compound of Embodiment 1, wherein the compound of Formula (I) is selected from the group consisting of: , . the compound of Formula (I) is selected from the group consisting of: R 4 2), 2).
  • R 1 is selected from the group consisting of: - 106 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) , wherein R 5a , R 5b , R 5c , R 5d , selected from the group consisting of H, halogen, , substituted C 1 -C 6 alkyl, optionally substituted C6-C10 aryl, and optionally substituted C2-C10 heteroaryl.
  • Embodiment 5 provides the compound of Embodiment 4, wherein at least one of R 5a , R 5b , R 5c , R 5d , and R 5e is phenyl, optionally wherein the phenyl is substituted with at least one selected from the group consisting of OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkyl, and C1-C6 haloalkyl.
  • Embodiment 6 provides the compound of Embodiment 4 or 5, wherein R 5a , R 5b , R 5c , R 5d , and R 5e , if present, are each independently selected from the group consisting of H, CH3, .
  • Embodiment 10 provides the compound of Embodiment of 9, wherein R 6a , R 6b , R 6c , R 6d , and R 6e are each independently selected from the group consisting of H, F, and Cl, optionally wherein one of R 6a , R 6b , R 6c , R 6d , and R 6e is F or Cl.
  • Embodiments 1-12 provides the compound of any one of Embodiments 1-12, which is selected from the group consisting of: 4-(3-(4-chlorophenyl)-4-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)piperazine-1- carbonyl)-N-methylbenzamide; - 108 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) (S)-4-(3-(4-chlorophenyl)-4-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)piperazine-1- carbonyl)-N-methylbenzamide; (R)-4-(3-(4-chlorophenyl)-4-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)piperazine- 1-carbonyl)-N-methylbenzamide; 2-(4-fluorophenyl)-1-((2
  • Embodiment 15 provides the compound of Embodiment 14, wherein at least one of the following applies: (a) at least one of R 7a , R 7b , R 7c , and R 7d is H; (b) at least two of R 7a , R 7b , R 7c , and R 7d are H; (c) at least three of R 7a , R 7b , R 7c , and R 7d are H; and (d) each of R 7a , R 7b , R 7c , and R 7d are H.
  • Embodiment 16 provides the compound of Embodiment 14 or 15, wherein each occurrence of R 7e and R 7f is independently selected from the group consisting of H, CH 3 , .
  • Embodiments 14-16 wherein R 8 is phenyl optionally substituted with at least one halogen.
  • Embodiment 18 provides the compound of any one of Embodiments 14-17, wherein R 8 is selected from the group consisting of phenyl, 4-chlorophenyl, and 4-fluorophenyl.
  • Embodiment 19 provides the compound of any one of Embodiments 14-18, wherein - 114 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) L 3 is selected from the group consisting of a bond, -(CH2)-, -(CHCH3)-, - .
  • Embodiment 21 provides the compound of Embodiment 20, wherein the phenyl, naphthyl, or indolyl is optionally substituted with at least one C1-C6 haloalkyl, optionally wherein the haloalkyl is CF 3 .
  • Embodiment 22 provides the compound of any one of Embodiments 14-21, wherein , , .
  • R 10a and R 10b are each independently selected from the group consisting of H, C1-C6 alkyl, and optionally substituted C 3 -C 6 cycloalkyl, optionally wherein R 10a and R 10b are each - 115 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) independently selected from the group consisting of H, CH3, .
  • Embodiment 27 provides a pharmaceutical composition comprising at least one compound of any one of Embodiments 1-26 and a pharmaceutically acceptable carrier or excipient.
  • Embodiment 28 provides the pharmaceutical composition of Embodiment 27, further comprising at least one additional agent suitable for treating, preventing, and/or ameliorating a bacterial infection.
  • Embodiment 29 provides the pharmaceutical composition of Embodiment 28, wherein the at least one additional agent suitable for treating, preventing, and/or ameliorating a - 118 - 55708207.3
  • Attorney Docket No.046641-7064WO1(00175) bacterial infection is selected from the group consisting of a polymyxin, aminoglycoside, ⁇ - lactam (e.g., penicillin, cephalosporin, or carbapenem), monobactam, fluoroquinolone, sulfonamide, tetracycline, and macrolide.
  • Embodiment 30 provides the pharmaceutical composition of Embodiment 28 or 29, wherein the additional agent suitable for treating, preventing, and/or ameliorating a bacterial infection is at least one selected from the group consisting of colistin (polymyxin E), polymyxin B, amikacin, ampicillin, amoxicillin aminoglycoside, azithromycin, aztreonam, carbapenem, cefepime, cefiderocol, cefotaxime, ceftriaxone, ceftaroline, ceftazidime, ceftobiprole, ceftolozane, ciprofloxacin, clindamycin, dalbavancin, daptomycin, doxycycline, ertapenem, fluoroquinolone, gentamicin, imipenem, levofloxacin, linezolid, meropenem, minocycline, mupirocin, oritavancin, piperacillin
  • Embodiment 31 provides a method of treating, preventing, and/or ameliorating a bacterial infection in a subject, the method comprising administering to the subject: (a) at least one compound of any one of Embodiments 1-26 or the pharmaceutical composition of any one of Embodiments 27-30; and (b) at least one polymyxin antibiotic, or an analogue or derivative thereof.
  • Embodiment 32 provides a method of sensitizing a bacterial colony to at least one antibiotic polypeptide, the method comprising contacting the bacterial colony with at least one compound of any one of Embodiments 1-26, or the pharmaceutical composition of any one of Embodiments 27-30.
  • Embodiment 33 provides the method of Embodiment 31 or 32, wherein the antibiotic peptide is at least one selected from the group consisting of a polymyxin antibiotic and a defensin, optionally wherein the polymyxin antibiotic is selected from the group consisting of colistin (polymyxin E) and polymyxin B.
  • the antibiotic peptide is at least one selected from the group consisting of a polymyxin antibiotic and a defensin, optionally wherein the polymyxin antibiotic is selected from the group consisting of colistin (polymyxin E) and polymyxin B.
  • Embodiment 34 provides the method of any one of Embodiments 31-33, wherein the bacterial infection or bacterial colony comprises a bacterial species selected from the group consisting of: Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus lugdenensis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus saprophyticus, Staphylococcus simulans, Staphylococcus warnerii, Staphylococcus capitis, Staphylococcus caprae, Staphylococcus pettenkoferi, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus pneumoniae, Group C streptococci, Streptococcus constellatus, Enterococcus faecalis, Enterococcus faecium, Corynebacterium jeikeium, Lac
  • Embodiment 35 provides the method of any one of Embodiments 31-34, wherein the method further comprises administering at least one additional antibiotic.
  • Embodiment 36 provides the method of Embodiment 35, wherein the additional antibiotic is at least one selected from the group consisting of a aminoglycoside, ⁇ -lactam (e.g., penicillin, cephalosporin, or carbapenem), monobactam, fluoroquinolone, sulfonamide, tetracycline, and macrolide.
  • ⁇ -lactam e.g., penicillin, cephalosporin, or carbapenem
  • monobactam e.g., fluoroquinolone, sulfonamide, tetracycline, and macrolide.
  • Embodiment 37 provides the method of Embodiment 35 or 36, wherein the additional antibiotic is at least one selected from the group consisting of amikacin, aminoglycoside, azithromycin, aztreonam, carbapenem, cefepime, ceftriaxone, ceftaroline, ceftazidime, ceftobiprole, ceftolozane, ciprofloxacin, clindamycin, dalbavancin, daptomycin, doxycycline, ertapenem, fluoroquinolone, gentamicin, imipenem, levofloxacin, linezolid, meropenem, minocycline, mupirocin, oritavancin, piperacillin, streptogramin, tedizolid, telavancin, tigecycline, ticarcillin, tobramycin, trimethoprim/sulfamethoxazole, and vancomycin
  • Embodiment 38 provides the method of any one of Embodiments 31 and 33-37, wherein the bacterial infection is a persistent or antibiotic resistant bacterial infection.
  • Embodiment 39 provides the method of any one of Embodiments 31-38, wherein formation of a bacterial biofilm is at least partially prevented or inhibited.
  • Embodiment 40 provides the method of any one of Embodiments 31 and 33-39, wherein the infection occurs on a prosthesis or an implant.
  • Embodiment 41 provides the method of Embodiment 40, wherein the prosthesis selected from the group consisting of a knee prosthesis, a hip prosthesis, elbow prosthesis, ankle prosthesis, shoulder prosthesis, and spine prosthesis.
  • Embodiment 42 provides the method of any one of Embodiments 31 and 33-41, wherein the subject is a mammal.
  • Embodiment 43 provides the method of any one of Embodiments 31 and 33-42, wherein the subject is a human.
  • the terms and expressions employed herein are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the embodiments of the present application.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

In certain aspects, the disclosure relates to mobilized colistin resistance (MCR) enzyme (MCR-1) inhibitors, pharmaceutical compositions thereof, and methods of use thereof for treating, preventing, and/or ameliorating bacterial infections and/or sensitizing bacteria to polymyxin antibiotics.

Description

Attorney Docket No.046641-7064WO1(00175) TITLE Inhibitors of Mobilized Colistin Resistance Enzyme (MCR-1) and Methods of Use Thereof CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No.63/660,713, filed June 17, 2024, which is incorporated herein by reference in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under grant AI168780 awarded by the National Institute of Allergy and Infectious Disease (NIAID). The government has certain rights in the invention. BACKGROUND The increasing prevalence of antibiotic resistance among bacterial pathogens is a serious threat to global health. A particular problem is the spread of multidrug-resistant (MDR) Gram-negative bacterial infections. The rapid increase in carbapenem-resistant and MDR Enterobacterales that produce carbapenemase enzymes such as Klebsiella pneumoniae carbapenemase (KPC) and New Delhi metallo-β-lactamase (NDM) has created challenges for treatment. Due to the paucity of novel antibiotics, polymyxins (colistin, polymyxin B), although introduced in the 1950s, have gained renewed interest for treating infections due to multidrug-resistant bacteria and are a last resort antibiotic. Polymyxins are cationic polypeptides that act by binding to the lipid A moiety of bacterial lipopolysaccharide (LPS) and subsequently disrupting the bacterial membrane. Acquired and chromosome-encoded resistance to colistin has been reported among Gram-negative bacteria and some species, such as Neisseria spp., are intrinsically resistant to colistin. The most common mechanism of acquired resistance involves modification of the LPS component of the outer membrane. Specifically, resistance occurs due to modification of the 1 and 4’ phosphate groups of lipid A to neutralize the negative charge and reduce binding of the positively charged colistin. The phosphates are modified with 4-amino-arabinose by the aminoarabinose transferase ArnT or by addition of phosphoethanolamine (PEA) by PEA transferase enzymes. Chromosome encoded and acquired resistance to polymyxins is associated with mutations found in genes for two-component regulatory systems and result in - 1 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) expression of the transferase enzymes that modify LPS. The X-ray structures of an ArnT transferase as well as the Neisseria meningitidis (NmEptA) and the catalytic domain of Campylobacter jejuni (EptC) PEA transferases have been determined. ArnT is a membrane protein with a periplasmic domain and is a glycosyltransferase. The PEA transferases also have a membrane-spanning domain and a periplasmic catalytic domain. The catalytic domain of the NmEptA and EptC PEA transferases have a similar structure and are members of the sulfatase group with a fold similar to alkaline phosphatase. The acquisition of polymyxin resistance through chromosomal mutations is not transferable. In 2016, however, a plasmid- encoded LPS-modifying enzyme, named MCR-1, which provides colistin resistance was reported from Enterobacterales in China. This is a source of concern since it provides transferrable resistance to polymyxin antibiotics. It raises the spectre of transferable pandrug resistance in Enterobacterales. Indeed, there are numerous reports of the spread of the mcr-1 gene worldwide in community- and hospital-acquired pathogens. Also, the mcr-1 gene has been found in patient and animal sources in the United States. The threat of the MCR-1 enzyme to the efficacy of antibiotic therapy makes the discovery of inhibitors for this enzyme an urgent need. Thus, there is a need in the art for compounds and methods for preventing or reducing the onset of resistance to polymyxin antibiotics. The disclosure addresses this need. BRIEF SUMMARY In one aspect, the disclosure provides a compound of Formula (I), or a salt, solvate, stereoisomer, or isotopologue thereof, wherein R1, R2a, R2b, R2c, R2d, R2e, R2f, L1, L2, and X1 are defined elsewhere herein: . In another aspect, the of Formula (II), or a salt, solvate, stereoisomer, or isotopologue thereof, wherein R7a, R7b, R7d, R8, R9, R10a, R10b, X2, X3, Y1, Y2, L3, and L4 are defined elsewhere herein: - 2 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) . In another aspect, composition comprising at least one compound of the carrier or excipient. In another aspect, the disclosure provides a method of treating, preventing, and/or ameliorating a bacterial infection in a subject. In certain embodiments, the method comprises administering to the subject at least one compound of the disclosure, or a pharmaceutical composition thereof, and at least one polymyxin antibiotic, or an analogue or derivative thereof. BRIEF DESCRIPTION OF THE FIGURES The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments of the present application. The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. FIG.1 shows the structure of lipid A of E. coli showing reaction catalyzed by PEA transferases such as MCR-1. Phosphatidylethanolamine typically has acyl chains of C12 and C14 at positions R1 and R2, respectively. The PEA moiety that is transferred to lipid A is shown. Transfer occurs at the 4′ or 1-position of lipid A. FIGs.2A-2B show the structure of NmEptA solved by X-ray crystallography. FIG 2A shows a ribbon diagram of NmEptA. Dodecyl-β-D-maltoside (DDM) shown as spheres. FIG. 2B shows the active site with DDM. Key residues are labeled. The catalytic zinc is shown as a sphere. Helices PH2 and PH2’ are at the border of the active site and membrane domain. FIG.3 shows the DECL process. Key steps for this proposal include 1) creation and encoding of the DNA-encoded compounds, 2) selection of the libraries against MCR-1, 3) isolation of the small molecules binders, and 4) sequencing of the DNA barcodes to decode the molecular structures of the binders. FIG.4 shows sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS- PAGE) of purified fractions of full length MCR-1 (62 kDa). FIG.5A shows schematic of enzyme-catalyzed removal of phosphoethanolamine - 3 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) from fluorescently labeled phosphotidylethanolamine substrate (NDB-PEA) to create product NDB-DG. FIG.5B shows thin-layer chromatography (TLC) of reaction products. Positions of NBD-PEA and NDB-DG are labeled. CT is a no enzyme control TLC. FIG.6 shows compounds initially identified compounds CDD-1794 and CDD-1938. FIGs.7A-7F show spot test for E. coli growth with colistin and CDD-1938. Overnight (O/N) cultures of E. coli containing WT MCR-1 or MCR T285A were spotted (10μl) onto agar plates with no dilution and 10-fold serial dilutions 7A shows control result. FIG.7B shows 25 μM CDD-1938 with no colistin. FIG.7C shows .0.8 μg/ml colistin, no CDD-1938. FIG.7D shows 0.8 μg/ml colistin with 3.1 μM CDD-1938. FIG.7E shows 0.8 μg/ml colistin with 6.3 μM CDD-1938. FIG.7F shows 0.8 μg/ml colistin with 12.5 μM CDD-1938. FIGs.8A-8B: docking results of CDD-1794 and CDD-1938 to MCR-1 homology model. FIG.8A shows CDD-1794 docked in MCR-1 model. CDD-1794 is in a pocket adjacent to the active site Zn and catalytic Thr285. FIG.8B shows CDD-1938 docked in MCR-1 homology model. Without being bound by theory, CDD-1938 is postulated to occupy the same site as CDD-1794. FIG.9 shows structure-activity relationships for CDD-1938. Schematic of the DECL hit based on DNA sequencing. The linker, cycle 1, building block position (C1). Cycle 2 (C2) and 3 (C3) building block positions are shown. B-M are molecular analogs of CDD-1938. Compound names and potency based on comparison to colistin alone in the spot assay are shown. Cytotoxicity as indicated by IC50 for HepG2 cells is shown for select compounds. FIG.10 shows colistin MIC values for E. coli expressing MCR-1 in the presence of inhibitor compounds of the disclosure. MICs shown on Y-axis in log2 scale. Compound concentrations indicated on X-axis. Compounds are indicated in the inset. FIG.11 shows spot test assay for CDD compounds against MCR-1 mediated colistin resistant clinical isolates. The top row shows the spot test for agar plates containing 0.8 μg/ml colistin. The bottom two rows show spot test results using agar plates containing 0.8 mg/ml colistin and 12.5 μM CDD compound. Each strain was tested in duplicate. The spots on each plate are a non-diluted overnight culture on the far right and 10-fold serial dilutions proceeding right to left. The strains corresponding to each row of spots are labeled. WT-1 and WT-2 represent the duplicates of E. coli XL1-Blue containing MCR-1. The clinical strains and duplicates are labeled. Each column of plates corresponds to the compound tested as indicated below the columns. The columns are arranged from most potent compound on the right to least potent on the left. FIG.12 shows structure-activity relationships for analogs based on the high potency - 4 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) CDD-2901 and CDD-2847 compounds. Compound names and potency based on comparison to colistin alone in the spot assay are shown. Cytotoxicity as indicated by IC50 for HepG2 cells is shown for select compounds. FIG.13 shows a summary of structure-activity relationships based on analogs of CDD-1794. FIG.14: Catalytically functional MCR-1 is necessary for protection against colistin in E. coli. Time-kill curve of E. coli expressing wild type and catalytically inactive mutant T285A MCR-1 from a plasmid in the absence of and increasing concentrations of colistin sulfate (2 µg/ml, 4 µg/mL and 8 µg/mL) measured up to 6 hours. The data represent one independent experiment performed using technical replicates. Error bars represent standard error means. Overnight cultures were normalized and diluted to 104 CFUs/mL and using a 96-well format were pre-incubated for 45 min and then treated with colistin. Cultures were grown in Luria Bertani (LB) broth with 12.5 µg/mL chloramphenicol. Similar results were found in cation-adjusted Mueller Hinton (CAMH) broth. CFU = colony forming units. FIGs.15A-15D: Structures of DNA-encoded chemical library (DECL) hits and analogs with activity against MCR-1. Activity of the compounds with or without colistin against E. coli/WT MCR-1 growth was tested using the spot assay and minimum inhibitory concentration (MIC) method, respective values determined at 12.5 µg/mL compound concentration are indicated under each compound structure. For the spot assay method, colistin was set at 0.32 µg/mL and scored based on the fold difference (X) between growth with colistin alone vs colistin/compound combination; while for MIC, colistin was tested from 0-32 µg/mL and 12.5 µg/mL compound. FIG.15A: Structure of DECL screening hit CDD-1938. This racemic mixture was identified through affinity-based selection of a DECL of 2 million compounds against purified WT MCR-1 His-tagged enzyme. FIG.15B: Structure of DECL screening hit CDD-3358. This compound was also identified through affinity-based selection of a DECL of 2 million compounds against purified WT MCR-1 enzyme, and a truncated version of the CDD-3358 compound, CDD-1794, was synthesized and tested due to difficulties in resynthesizing CDD-3358. FIG.15C: Structures of potent inhibitor analogs derived from the original DECL hit, CDD-1938. This is a representative subset of the series that was generated to enhance the bioactivity of CDD-1938 by modifying the four regions (linker, the cycle 1 (C1), cycle 2 (C2), cycle 3 (C3) building blocks) branched to one another around the central piperazine ring of C1 building block in CDD- 1938. FIG.15D: Structure of a potent inhibitor analog derived from the original DECL truncated hit, CDD-1794. This lead inhibitor evolved from a series of analogs that were - 5 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) optimized by modifying the C1, C2 and C3 building blocks to enhance bioactivity of CDD- 1794. FIGs.16A-16B: MCR-1 protects E. coli from colistin killing. FIG.16A: DNA- encoded chemical library (DECL) screening hits block the catalytic activity of MCR-1 and resensitize bacteria to colistin killing. Spot assay experiments for E. coli containing wild- type MCR-1 (1) and T285A MCR-1 (2) expressed from a plasmid also conferring chloramphenicol (Cm) resistance were performed. E. coli strains were grown overnight in LB media containing Cm (12.5 µg/mL), normalized, diluted (10-1 through 10-6) and spotted on LB media containing Cm (12.5 µg/mL): media control, or LB + Cm with a sub-inhibitory concentration of colistin sodium methane sulfonate (0.32 µg/mL), or with a high (12.5 µM) concentration of inhibitor only and with both 0.32 µg/mL colistin and low (3.125 µM), medium (6.25 µM) or high (12.5 µM) concentrations of inhibitors CDD-1938 and CDD- 1794. All inhibitor only controls were similar to the representative inhibitor, CDD-1938, and media only controls shown in the chart. All spot data for colistin and inhibitor (low, medium, high) combinations for E. coli T285A MCR-1 were the same and shown as one representative example for colistin/CDD-1938 or colistin/CDD-1794. Experiments were performed with biological triplicates for E. coli/WT MCR-1 and E. coli/T285A MCR-1, two or more independent experiments were carried out. ON, overnight; Ctrl, control. FIG.16B: Concentration-dependent activity of MCR-1 inhibitors. Colistin minimum inhibitory concentrations (µg/mL) for E. coli containing a plasmid encoding wild-type MCR-1 or T285A MCR-1 were performed in cation-adjusted Mueller-Hinton broth + Cm (12.5 µg/mL) using 2-fold microdilutions from 0-32 µg/mL of colistin sulfate and 2-fold microdilutions from 0-100 µM of CDD-1794 and CDD-1938 inhibitors. Cmpd, compound. ND, not determined. FIG.17: Optimized inhibitors show improved potency against MCR-1 and resensitize bacteria to colistin killing. Spot assay experiments for E. coli containing wild-type MCR-1 (1) and T285A MCR-1 (2) expressed from a plasmid also conferring chloramphenicol (Cm) resistance were performed. E. coli strains were grown overnight in LB media containing Cm (12.5 µg/mL), normalized, diluted (10-1 through 10-6) and spotted on LB media containing Cm (12.5 µg/mL): media control, or LB + Cm with a sub-inhibitory concentration of colistin sodium methane sulfonate (0.32 µg/mL), or with a high (12.5 µM) concentration of inhibitor only and with both 0.32 µg/mL colistin and high (12.5 µM) concentrations of inhibitors: CDD-2750, CDD-2847, CDD-3002, CDD-2902, CDD-3003, and CDD-3356. All inhibitor only controls were similar to the representative inhibitor, CDD-2750, and media only controls - 6 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) shown in the chart. Experiments were performed with biological triplicates for E. coli/WT MCR-1 and E. coli/T285A MCR-1, two or more independent experiments were carried out. ON, overnight; Ctrl, control. FIGs.18A-18B: Colistin MIC values for E. coli expressing MCR-1 in the absence and presence of inhibitor compounds. FIG.18A: Colistin sulfate MIC values in the absence and presence of inhibitor compounds from screening hits and their optimized analogs for E. coli/WT MCR-1 grown in cation-adjusted Mueller-Hinton broth and chloramphenicol (12.5 µg/mL). NA, not available. Data is representative of several independent experiments. FIG. 18B: A graphic representation of the MICs shown on the Y-axis in log2 scale and compound concentrations are indicated on the X-axis. Compounds tested are indicated in the inset. Error bars represent standard error mean. FIG.19: MCR-1 inhibitors are active against Enterobacterales clinical isolates containing MCR-1 and MCR-2. Spot assay results for CDD-2901, CDD-2750, CDD-3002, CDD-2918, CDD-2902, CDD-3019 and CDD-2847, in combination with colistin compared to colistin-only results. Plates are shown in ascending order of colistin/inhibitor potency against E. coli/WT MCR-1 and CDC-validated mcr-1+ K. pneumoniae (0497) and mcr-1+ E. coli (0495, 0346, 0493) and mcr-2+ E. coli (0538, purple) clinical isolates. Duplicates for strains spotted and tested on the plates are indicated as “-1” and “-2”. FIGs.20A-20B: Time-kill curve for E. coli expressing WT MCR-1 against 4 µg/mL colistin sulfate (CS) in the presence and absence of two different chemotypes: optimized inhibitors CDD-3003 and CDD-3356. The plots represent two independent experiments performed in duplicate and are representative of additional time-kill curve plots tested for the same combinations performed in cation-adjusted Mueller-Hinton broth in a 96-well format at 37°C, 350 rpm orbital shaking. FIG.20A: Time-kill analysis of various treatments with inhibitor CDD-3003 as described in the inset. FIG.20B: Time-kill analysis of various treatments with inhibitor CDD-3356 as described in the inset. Unidirectional error bars, for clarity, represent the standard error mean. FIGs.21A-21C: Comparison of MCR-1 and its variants using AlphaFold2. FIG.21A: Superposition of the predicted full-length MCR-1 from E. coli (PDB entry: AF- A0A0R6L508, average pLDDT = 93.6, 543 residues) and MCR-3 from K. pneumoniae (PDB entry: AF-A0A5P5X6L1, average pLDDT = 93, 543 residues). They share 33% amino acid. FIG.21B: Superposition of the predicted full-length MCR-1 and MCR-5 from Aeromonas hydrophila subsp. hydrophila (PDB entry: A0A2H4N789, average pLDDT = 92.06, 549 residues). They share 34.3% amino acid identity. FIG.21C: Superposition of the predicted - 7 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) full-length MCR-1 and MCR-9 from Enterobacter hormaechei (PDB entry: AF- A0A2J0QUR8, average pLDDT = 94.12, 542 residues). They share 35.1% amino acid identity. Pairwise sequence alignments were carried out using EMBOSS Needle. FIG.22: Catalytically functional MCR-1 is necessary for protection against colistin in E. coli. Time-kill curve of E. coli expressing wild type and catalytically inactive mutant T285A MCR-1 from a plasmid in the absence of and increasing concentrations of colistin sulfate (2 µg/ml, 4 µg/mL and 8 µg/mL) measured up to 24 hours. The data represent one independent experiment performed using technical replicates. Error bars represent standard error means. Overnight cultures were normalized and diluted to 104 CFUs/mL and using a 96-well format were pre-incubated for 45 min and then treated with colistin. Cultures were grown in Luria Bertani (LB) broth with 12.5 µg/mL chloramphenicol. Similar results were found in cation-adjusted Mueller Hinton (CAMH) broth. CFU = colony forming units. FIG.23: Optimized inhibitor shows activity against select mcr-1+ E. coli clinical isolates and partially resensitizes these bacteria to colistin killing. Spot assay experiments for laboratory E. coli containing wild-type MCR-1 (1) and T285A MCR-1 (2) expressed from a plasmid also conferring chloramphenicol (Cm) resistance as controls and mcr-1+ E. coli clinical isolates were performed. E. coli clinical isolates: #107 (3), #109 (4), #240 (5), #6770 (6), #9824 (7), #9991 (8) and #10618 (9) were obtained. The laboratory strains were grown overnight in LB media containing Cm (12.5 µg/mL) and E. coli clinical isolates were grown in LB media; all strains were normalized, diluted (10-1 through 10-6) and spotted on LB agar containing Cm (12.5 µg/mL) or LB agar as a media control, or LB + Cm with a sub- inhibitory concentration of colistin sodium methane sulfonate (0.32 µg/mL), or with a high (12.5 µM) concentration of inhibitor only and with both 0.32 µg/mL colistin and high (12.5 µM) concentrations of inhibitors, CDD-2750. All media only and inhibitor only controls were similar among the clinical isolates shown in the chart. Experiments were performed with biological duplicates in technical replicates for all strains. ON, overnight; Ctrl, control. Photos were taken through the Petri dish cover lid through a BSL2 cabinet window; so, controls appear faint. FIGs.24A-24B: Time-kill curve analysis for E. coli expressing WT MCR-1 against 4 µg/mL colistin sulfate (CS) in the presence and absence of the racemic mixture, CDD-3366, and its S-enantiomer, CDD-3356. FIG.24A: Various concentrations of racemic mixture, CDD-3366, combined with 4 µg/mL CS were tested against E. coli/WT MCR-1 in cation- adjusted Mueller-Hinton (CAMH) + chloramphenicol (Cm) (12.5 µg/mL) grown at 37°C for 4.5 hours. FIG.24B: Various concentrations of S-enantiomer, CDD-3356, combined with 4 - 8 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) µg/mLCS were tested against E. coli/WT MCR-1 in CAMH + Cm (12.5 µg/mL) grown at 37°C for 4.5 hours. Data represents one independent experiment performed in duplicate. Unidirectional error bars, for clarity, represent the standard error mean. FIGs.25A-25B: Structural comparison of MCR-1, NmEptA and PmrC. FIG.25A: Superposition of the AlphaFold2 predicted full-length MCR-1 from E. coli (PDB entry: A0A0R6L508, average pLDDT = 93.6, 543 aa) and crystal structure of EptA from Neisseria meningitidis (PDB entry: 5FGN, 554aa without the Hisx6 tag). They share 37.6% amino acid identity. FIG.25B: Superposition of the Alphafold2 predicted full-length MCR-1 from E. coli and PmrC from A. baumannii (PDB entry: A0A7D5YE97, average pLDDT – 92.69, 551 aa). They share 32.7% amino acid identity. Pairwise sequence alignments were carried out using EMBOSS Needle. FIG.26: Analog series of chemotype 1, CDD-1938, showing varied bioactivity. Spot assay score defines the difference in growth between colistin-only treatment vs colistin/MCR-1 inhibitor treatment; it is described as a fold difference. Data shown here are representative of multiple (2-4) experiments. Where there are ranges, both values were identified several times in multiple experiments. FIG.27: Analog series of chemotype 2, CDD-1794, showing varied bioactivity. Spot assay score defines the difference in growth between colistin-only treatment vs colistin/MCR-1 inhibitor treatment; it is described as a fold difference. Data shown are representative of multiple (2-4) experiments. Where there are ranges, both values were identified several times in multiple experiments. DETAILED DESCRIPTION Reference will now be made in detail to certain embodiments of the disclosed subject matter, examples of which are illustrated in part in the accompanying drawings. While the disclosed subject matter will be described in conjunction with the enumerated claims, it will be understood that the exemplified subject matter is not intended to limit the claims to the disclosed subject matter. Throughout this document, values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a range of “about 0.1% to about 5%” or “about 0.1% to 5%” should be interpreted to include not just about 0.1% to about 5%, but also the individual values (e.g., 1%, 2%, 3%, and 4%) - 9 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) and the sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. The statement “about X to Y” has the same meaning as “about X to about Y,” unless indicated otherwise. Likewise, the statement “about X, Y, or about Z” has the same meaning as “about X, about Y, or about Z,” unless indicated otherwise. In this document, the terms “a,” “an,” or “the” are used to include one or more than one unless the context clearly dictates otherwise. The term “or” is used to refer to a nonexclusive “or” unless otherwise indicated. The statement “at least one of A and B” or “at least one of A or B” has the same meaning as “A, B, or A and B.” In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting; information that is relevant to a section heading may occur within or outside of that particular section. All publications, patents, and patent documents referred to in this document are incorporated by reference herein in their entirety, as though individually incorporated by reference. In the event of inconsistent usages between this document and those documents so incorporated by reference, the usage in the incorporated reference should be considered supplementary to that of this document; for irreconcilable inconsistencies, the usage in this document controls. In the methods described herein, the acts can be carried out in any order, except when a temporal or operational sequence is explicitly recited. Furthermore, specified acts can be carried out concurrently unless explicit claim language recites that they be carried out separately. For example, a claimed act of doing X and a claimed act of doing Y can be conducted simultaneously within a single operation, and the resulting process will fall within the literal scope of the claimed process. Description Antimicrobials are the bedrock of modern medicine. However, the rapid evolution and dissemination of antimicrobial resistance (AMR) threatens to restrict their use, and as a result, society may be entering a post-antibiotic era. It is predicted that 39.1 million humans will die globally from antibiotic resistance between 2025 and 2050, which is an estimated 70% increase in global deaths attributable to AMR in the coming decades. With an average development cost of greater than $1 billion and 10-15 years development time needed for a new antibiotic, there is a pressing need for innovative and sustainable strategies that will stay ahead of the pace of resistance. Currently, old antibiotics, such as polymyxins, despite their nephrotoxicity and neurotoxicity, have been reintroduced as last-resort antibiotics to combat - 10 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) the global emergence of carbapenem-resistant, multi-drug resistant Enterobacterales as there are no new antibiotics to treat these infections. Polymyxins, biosynthesized as secondary metabolites by the Gram-positive bacterium Paenibacillus polymyxa, are cationic cyclic lipo- decapeptides and have a narrow bactericidal activity spectrum against the common Gram- negative Enterobacterales. Polymyxin E, also known as colistin, and polymyxin B are the most studied and clinically used forms. They act predominantly by targeting the anionic lipid A component of the lipopolysaccharide (LPS) present in the outer membrane (OM) of Gram- negative bacteria causing membrane destabilization, OM and inner membrane (IM) permeability, leakage of cellular contents, and ultimately cell death. Unfortunately, colistin resistance has already been identified in carbapenemase-producing, multidrug-resistant (MDR) or extensively drug-resistant (XDR) Gram-negative bacteria on the CDC and WHO priority threat lists. Colistin resistance is primarily mediated through a reduction of the electrostatic attraction between colistin and the Gram-negative OM. In some species, such as Neisseria spp. and Proteus mirabilis, intrinsic polymyxin resistance is associated with the constitutive expression of chromosomal genes encoding transferase enzymes, such as ArnT, EptA (also known as PmrC), and EptC. Aminoarabinose transferase, ArnT, modifies the 1’- and 4’- anionic phosphate groups of the glucosamine moieties of lipid A in LPS with cationic 4- amino-4-deoxy-L-arabinose (L-Ara4N) and the phosphoethanolamine (pEtN) transferase, EptA, modifies the phosphate with a cationic pEtN. Either of these cationic additions reduce the net anionic charge of the cell surface to minimize binding of the positively-charged polymyxin. Until 2015, colistin resistance was thought to be the result of intrinsic resistance and acquired chromosomal mutations in several operons and genes associated with LPS membrane modifications and efflux pumps (e.g. phoPQ, pmrAB, mgrB, arnBCADTEF, pmrF operon, acrB). The non-transferable nature of this colistin resistance confined its clinical impact to localized outbreaks. Unfortunately, the unregulated use in animal production and its more recent use in clinical practice has contributed to a concerning rise in colistin-resistant clinical isolates, which has been associated with the rapid global dissemination of the plasmid-borne mobile colistin-resistance (mcr-1) gene. The mcr-1 gene, an ortholog of eptA (pmrC), also encodes a pEtN transferase and confers colistin resistance through the addition of pEtN from phosphatidylethanolamine, a naturally occurring phospholipid, to the 1’- or 4’- phosphate group of lipid A component of LPS as it is trafficked through the IM on the way to the OM. To date, ten mcr genes and their variants have been reported among various Enterobacterales organisms as well as community and environmental isolates. These variants - 11 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) are PEA transferases that confer colistin resistance and share 32-88% amino acid identity with MCR-1, which remains the most predominant type in clinical isolates. Although amino acid sequence differences are large among the mcr variants (e.g., 33%), AlphaFold2 structure predictions show a conserved structure among the variants (FIGs.21A-21C). Specifically concerning are those multidrug-resistant (MDR) strains harboring mcr-1 alongside extended- spectrum beta-lactamase and carbapenemase resistance genes. Clearly, the spread of mcr-1 threatens to decrease the clinical utility of colistin as a last resort antibiotic, and we need to explore new approaches to colistin therapy. Various strategies have been explored to combat mcr-1+ strains and restore colistin efficacy, such as CRISPR/CAS-based tools to eliminate mcr-1 strains, mcr-1 plasmid conjugation inhibitors, MCR inhibitors, novel polymyxin derivatives, combination therapy using various antibacterial agents and non-antibiotic compounds. Significant attention has been focused on exploring colistin combination treatment options with multiple antibiotics. Described herein is an approach to extend the efficacy of colistin using combination therapy with a synergizing bioactive partner, in this case, an inhibitor of the important resistance determinant MCR-1. Currently, there are no clinically available inhibitors of MCR-1. This strategy has been used in combination therapies using beta-lactam antibiotics and beta-lactamase inhibitors and has proven clinically successful. To identify MCR-1 inhibitors, a DNA-encoded chemical libraries (DECL), a powerful tool to identify small-molecule binders to therapeutically relevant protein targets, was used. DECLs consist of very large collections of compounds, each coupled to distinctive DNA tags serving as amplifiable identification barcodes, which permit the retrieval and identification of binding compounds after screening. To date, novel ligands discovered by DECLs have resulted in three clinical candidates and multiple antibacterial hits. Tight binding inhibitors against the bacterial beta-lactamase enzymes OXA-48, NDM-1 as well as the viral SARS- CoV-2 main protease (Mpro), were recently identified using DECLs. Described herein is the successful use of DECLs for the discovery of novel inhibitors of the MCR-1 resistance enzyme. A DNA-encoded compound collection was created containing greater than 2 billion unique molecules. These libraries were assembled and screened in a single pool, allowing for the rapid identification of chemical ligands. The libraries were screened in a single experiment against purified MCR-1 enzyme that was immobilized to a magnetic bead. Several putative hit compounds were identified and synthesized in the absence of the DNA tag for subsequent testing. The chemically unique compounds were validated by determining their activity in microbiological assays in the absence and presence of colistin, and two - 12 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) unique chemotypes were found to synergize with colistin to kill E. coli expressing the MCR- 1 enzyme. Importantly, the compounds do not alter the growth rate of E. coli when used alone and do not synergize with colistin against E. coli containing a catalytically inactive MCR-1 protein, suggesting the compounds act through binding and inhibition of the active MCR-1 enzyme. Using structure-activity/toxicity relationship approaches, analogs were modified and optimized for enhanced bioactivity against E. coli expressing MCR-1 and mcr- 1+ and mcr-2+ MDR E. coli and Klebsiella pneumoniae isolates and show low cytotoxicity against human cells. In one aspect, the potent inhibitors of MCR-1 described herein restore the effectiveness of current and future polymyxin antibiotics as well as expand the availability of novel chemotypes for the antibacterial field. It is demonstrated herein that plasmid-encoded MCR-1 plays a critical role in conferring colistin resistance to laboratory E. coli (FIGs.14, 16A-16B, and 17) and clinical E. coli and K. pneumoniae isolates (FIG.19 and Table 9). Further, it is demonstrated that by blocking MCR-1 function in these strains with small-molecule inhibitors, identified using DECL technology, strains can be resensitized to the bactericidal activity of polymyxins (FIGs.15A-15D, 16A-16B, 17, 18A-18B, 19, and 20A-20B) and in doing so, safeguard the important action of these last-resort antibiotics. The inhibitors alone, do not affect resistance, indicating the effect is the result of the inhibitor/antibiotic combination. Regarding the mechanism of action, it is hypothesized herein that the colistin/inhibitor combination operates through self-promoted uptake of colistin as previously described, facilitating the entry of the lipophilic inhibitor across the OM and into the periplasm where it reaches the enzyme target, MCR-1, located in the IM. MCR-1 has been shown to protect the IM and confer resistance to polymyxins by modifying high levels of LPS with pEtN at the IM, thus repelling colistin from the IM. Once inside the periplasm, the inhibitor blocks MCR-1 activity allowing colistin to then, permeabilize the IM, trigger bacterial lysis and cause death. This natural self-uptake strategy, using colistin as a permeabilization aide, is also successfully exploited in a combination treatment with Gram-positive-specific antibiotics against mcr-1+ Enterobacterales in vitro. Following SAR optimization of two DECL screening hits and their analogs (90 compounds), two optimized chemotypes, CDD-3356 and CDD-3003, with low cytotoxicity to human cells, were identified and optimized. Both compounds in the presence of colistin reduce bacterial growth of an E. coli/MCR-1 laboratory strain by 100-fold compared to the colistin-only treatment as measured by spot assay (FIG.17) and by >16-fold as measured by MIC assay (FIG.18A and Table 9). The anti-infective efficacy of the two antibiotic/inhibitor - 13 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) combinations was also assessed using TKCs, where the rate of bactericidal killing was followed over a range of inhibitor concentrations and fixed colistin concentration. The TKC data for E. coli/MCR-1 indicate that both chemotypes, at their most effective concentrations (12.5 ^M), in combination with colistin, achieve complete bacterial killing by as early as 1.5 hours (CDD-3356/colistin) or 1 hour (CDD-3003/colistin) upon administration, which is up to 2.5 hours or 4 hours earlier to killing with colistin alone (FIGs.20A-20B). CDD-3356 and CDD-3003 both display a dose-dependent behavior, although it is more pronounced for CDD-3356. The best effective inhibitor concentrations, 6.25 and 12.5 ^M, combined with colistin are close to the goal to develop small-molecule compounds that inhibit MCR-1 in the 1 ^g/mL (2 ^M) range and effectively kill E. coli/MCR-1. Moreover, the antibacterial activity of these compounds also extends to MDR mcr-1+ K. pneumoniae clinical isolates by reducing growth by 16-fold (CDD-3356) or by 8-fold (CDD-3003), as measured by the microdilution method (Table 9). Inhibitors within the CDD-3003 chemotype series combined with colistin, although cytotoxic, also demonstrated inhibitory growth effects ranging from 102-105-fold against mcr-2+ E. coli and multiple mcr- 1+ E. coli clinical strains and, at best, 10-fold against mcr-1+ K. pneumoniae compared to colistin alone as measured using the spot assay (FIG.19). The lower range observed in MIC and spot assay values for the colistin/inhibitor combination among some of the clinical isolates tested, particularly K. pneumoniae, may be due to poor compound penetration. For example, K. pneumoniae release capsule polysaccharide to trap polymyxins and neutralize their bactericidal activity. Without wishing to be bound by any theory, this may be a reason why a reduction in potency of certain exemplary compounds is observed in the combination treatment against K. pneumoniae growth and could support the hypothesis that colistin in the colistin/inhibitor combination acts, in part, to potentiate inhibitor penetration across the OM by permeabilization. In some cases, instead of reducing colistin concentration in the presence of the inhibitor, it may be necessary to adjust colistin concentration while improving the accumulation of the inhibitor across the OM. The potency against colistin-resistant clinical E. coli isolates is encouraging as E. coli is one of the six leading pathogens responsible for deaths associated with antimicrobial resistance. In summary, using DECL technology, small-molecule compounds that specifically inhibit the function of resistance enzyme, MCR-1, a determinant important in the global transmissibility of colistin resistance in nosocomial pathogens, have been successfully identified and/or optimized. The disclosure demonstrates compound useful in a new - 14 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) approach to enhance the efficacy of polymyxins as a last resort antibiotic. Definitions The term “about” as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range, and includes the exact stated value or range. The term "acyl" as used herein refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom. The carbonyl carbon atom is bonded to a hydrogen forming a "formyl" group or is bonded to another carbon atom, which can be part of an alkyl, aryl, aralkyl cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group or the like. An acyl group can include 0 to about 12, 0 to about 20, or 0 to about 40 additional carbon atoms bonded to the carbonyl group. An acyl group can include double or triple bonds within the meaning herein. An acryloyl group is an example of an acyl group. An acyl group can also include heteroatoms within the meaning herein. A nicotinoyl group (pyridyl-3-carbonyl) is an example of an acyl group within the meaning herein. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and the like. When the group containing the carbon atom that is bonded to the carbonyl carbon atom contains a halogen, the group is termed a "haloacyl" group. An example is a trifluoroacetyl group. The term "alkenyl" as used herein refers to straight and branched chain and cyclic alkyl groups as defined herein, except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have from 2 to 40 carbon atoms, or 2 to about 20 carbon atoms, or 2 to 12 carbon atoms or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to vinyl, -CH=C=CCH2, -CH=CH(CH3), - CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others. The term "alkoxy" as used herein refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined herein. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. Examples of branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group can include about 1 to about 12, about 1 to about 20, or about 1 to about 40 carbon atoms bonded to the oxygen atom, and can further include double or triple - 15 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) bonds, and can also include heteroatoms. For example, an allyloxy group or a methoxyethoxy group is also an alkoxy group within the meaning herein, as is a methylenedioxy group in a context where two adjacent atoms of a structure are substituted therewith. The term "alkyl" as used herein refers to straight chain and branched alkyl groups and cycloalkyl groups having from 1 to 40 carbon atoms, 1 to about 20 carbon atoms, 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms. Examples of straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n- butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. As used herein, the term "alkyl" encompasses n-alkyl, isoalkyl, and anteisoalkyl groups as well as other branched chain forms of alkyl. Representative substituted alkyl groups can be substituted one or more times with any of the groups listed herein, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term "alkynyl" as used herein refers to straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to 40 carbon atoms, 2 to about 20 carbon atoms, or from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to – C^CH, -C^C(CH3), -C^C(CH2CH3), -CH2C^CH, -CH2C^C(CH3), and -CH2C^C(CH2CH3) among others. The term “antibiotic” refers to a compound or composition that kills or reduces the viability of a microorganism or inhibits the growth or proliferation of a microorganism. The term "amine" as used herein refers to primary, secondary, and tertiary amines having, e.g., the formula N(group)3 wherein each group can independently be H or non-H, such as alkyl, aryl, and the like. Amines include but are not limited to R-NH2, for example, alkylamines, arylamines, alkylarylamines; R2NH wherein each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines and the like; and R3N wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like. The term "amine" also includes ammonium ions as used herein. The term "amino group" as used herein refers to a substituent of the form -NH2, - NHR, -NR2, -NR3 +, wherein each R is independently selected, and protonated forms of each, - 16 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) except for -NR3+, which cannot be protonated. Accordingly, any compound substituted with an amino group can be viewed as an amine. An "amino group" within the meaning herein can be a primary, secondary, tertiary, or quaternary amino group. An "alkylamino" group includes a monoalkylamino, dialkylamino, and trialkylamino group. The term "aralkyl" as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein. Representative aralkyl groups include benzyl and phenylethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl. Aralkenyl groups are alkenyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein. The term "aryl" as used herein refers to cyclic aromatic hydrocarbon groups that do not contain heteroatoms in the ring. Thus aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups contain about 6 to about 14 carbons in the ring portions of the groups. Aryl groups can be unsubstituted or substituted, as defined herein. Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, a phenyl group substituted at any one or more of 2-, 3-, 4-, 5-, or 6-positions of the phenyl ring, or a naphthyl group substituted at any one or more of 2- to 8-positions thereof. The term “bacteria”, as used herein, refers to both prokaryotic and archaebacteria cellular organisms. “Bacteria” are unicellular microorganisms which have cell walls but lack organelles and an organized nucleus, including some that can cause disease. The term “bacterial colony” as used herein refers to growths of bacteria accumulated in distinct segments on solid materials or surfaces including agar plates, which in some cases includes cells from bacterial infection of a subject or host. A bacterial colony is derived from a common mother cell. The term “biofilm” as used herein refers to a chemical matrix produced to protect a bacteria or microorganism population. Biofilms are generally characterized as adhering to a surface and having a thin, slimy texture. Biofilms may grow in or on medical devices or prosthetic joints, or at other sites in tissue and organs. As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound described herein with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a - 17 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) patient or subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary and topical administration. The term "cycloalkyl" as used herein refers to cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group can have 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 4, 5, 6, or 7. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined herein. Representative substituted cycloalkyl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- or tri-substituted norbornyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term "cycloalkenyl" alone or in combination denotes a cyclic alkenyl group. A "disease" is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal's health continues to deteriorate. In contrast, a "disorder" in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal's state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal's state of health. As used herein, the terms "effective amount," "pharmaceutically effective amount" and "therapeutically effective amount" refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation. The terms "halo," "halogen," or "halide" group, as used herein, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. The term "haloalkyl" group, as used herein, includes mono-halo alkyl groups, poly- halo alkyl groups wherein all halo atoms can be the same or different, and per-halo alkyl - 18 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro. Examples of haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3- difluoropropyl, perfluorobutyl, and the like. The term "heteroaryl" as used herein refers to aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S; for instance, heteroaryl rings can have 5 to about 8-12 ring members. A heteroaryl group is a variety of a heterocyclyl group that possesses an aromatic electronic structure. A heteroaryl group designated as a C2-heteroaryl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise a C4-heteroaryl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups can be unsubstituted, or can be substituted with groups as is discussed herein. Representative substituted heteroaryl groups can be substituted one or more times with groups such as those listed herein. Additional examples of aryl and heteroaryl groups include but are not limited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N- hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3- anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl) , indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2-thiazolyl, 4- thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3- pyridazinyl, 4- pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6- quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5- isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7- - 19 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3- dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl), benzo[b]thiophenyl (2- benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6- benzo[b]thiophenyl, 7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl, (2-(2,3- dihydro-benzo[b]thiophenyl), 3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro- benzo[b]thiophenyl), 5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro- benzo[b]thiophenyl), 7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1- benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenz[b,f]azepine (5H-dibenz[b,f]azepin-1-yl, 5H-dibenz[b,f]azepine-2-yl, 5H-dibenz[b,f]azepine-3-yl, 5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine-5-yl), 10,11-dihydro-5H-dibenz[b,f]azepine (10,11-dihydro-5H-dibenz[b,f]azepine-1-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-2-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-3-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-4-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-5-yl), and the like. The term "heteroarylalkyl" as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined herein. The term "heterocyclylalkyl" as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group as defined herein is replaced with a bond to a heterocyclyl group as defined herein. Representative heterocyclyl alkyl groups include, but are not limited to, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl. The term "heterocyclyl" as used herein refers to aromatic and non-aromatic ring compounds containing three or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, and S. Thus, a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or if polycyclic, any combination thereof. In some embodiments, heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members. A heterocyclyl group designated as a C2-heterocyclyl can be a 5-ring with two - 20 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise a C4-heterocyclyl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms. A heterocyclyl ring can also include one or more double bonds. A heteroaryl ring is an embodiment of a heterocyclyl group. The phrase "heterocyclyl group" includes fused ring species including those that include fused aromatic and non-aromatic groups. For example, a dioxolanyl ring and a benzdioxolanyl ring system (methylenedioxyphenyl ring system) are both heterocyclyl groups within the meaning herein. The phrase also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. Heterocyclyl groups can be unsubstituted, or can be substituted as discussed herein. Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Representative substituted heterocyclyl groups can be mono-substituted or substituted more than once, such as, but not limited to, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or 6- substituted, or disubstituted with groups such as those listed herein. The term "hydrocarbon" or "hydrocarbyl" as used herein refers to a molecule or functional group that includes carbon and hydrogen atoms. The term can also refer to a molecule or functional group that normally includes both carbon and hydrogen atoms but wherein all the hydrogen atoms are substituted with other functional groups. As used herein, the term "hydrocarbyl" refers to a functional group derived from a straight chain, branched, or cyclic hydrocarbon, and can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl, acyl, or any combination thereof. Hydrocarbyl groups can be shown as (Ca- Cb)hydrocarbyl, wherein a and b are integers and mean having any of a to b number of carbon atoms. For example, (C1-C4)hydrocarbyl means the hydrocarbyl group can be methyl (C1), ethyl (C2), propyl (C3), or butyl (C4), and (C0-Cb)hydrocarbyl means in certain embodiments there is no hydrocarbyl group. The term "independently selected from" as used herein refers to referenced groups being the same, different, or a mixture thereof, unless the context clearly indicates otherwise. Thus, under this definition, the phrase "X1, X2, and X3 are independently selected from noble - 21 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) gases" would include the scenario where, for example, X1, X2, and X3 are all the same, where X1, X2, and X3 are all different, where X1 and X2 are the same but X3 is different, and other analogous permutations. The term “infection” as used herein refers to the onset of a disease by one or more pathogenic bacteria, including but not limited to Gram negative bacteria. The term "monovalent" as used herein refers to a substituent connecting via a single bond to a substituted molecule. When a substituent is monovalent, such as, for example, F or Cl, it is bonded to the atom it is substituting by a single bond. The term "organic group" as used herein refers to any carbon-containing functional group. Examples can include an oxygen-containing group such as an alkoxy group, aryloxy group, aralkyloxy group, oxo(carbonyl) group; a carboxyl group including a carboxylic acid, carboxylate, and a carboxylate ester; a sulfur-containing group such as an alkyl and aryl sulfide group; and other heteroatom-containing groups. Non-limiting examples of organic groups include OR, OOR, OC(O)N(R)2, CN, CF3, OCF3, R, C(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2)0- 2N(R)C(O)R, (CH2)0-2N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, C(=NOR)R, and substituted or unsubstituted (C1-C100)hydrocarbyl, wherein R can be hydrogen (in examples that include other carbon atoms) or a carbon-based moiety, and wherein the carbon-based moiety can be substituted or unsubstituted. The terms "patient," "subject," or "individual" are used interchangeably herein, and refer to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein. In a non-limiting embodiment, the patient, subject or individual is a human. As used herein, the term "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained. As used herein, the language "pharmaceutically acceptable salt" refers to a salt of the administered compounds prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids or bases, organic acids or bases, solvates, hydrates, or clathrates thereof. - 22 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric (including sulfate and hydrogen sulfate), and phosphoric acids (including hydrogen phosphate and dihydrogen phosphate). Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, malonic, saccharin, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2- hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric, salicylic, galactaric and galacturonic acid. Suitable pharmaceutically acceptable base addition salts of compounds described herein include, for example, ammonium salts, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N'-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared from the corresponding compound by reacting, for example, the appropriate acid or base with the compound. As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound described herein within or to the patient such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, including the compound(s) described herein, and not injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and - 23 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. As used herein, "pharmaceutically acceptable carrier" also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound(s) described herein, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. The "pharmaceutically acceptable carrier" may further include a pharmaceutically acceptable salt of the compound(s) described herein. Other additional ingredients that may be included in the pharmaceutical compositions used with the methods or compounds described herein are known in the art and described, for example in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference. The term “prosthesis” as used herein refers to an artificial body part. The term "room temperature" as used herein refers to a temperature of about 15 °C to 28 °C. The term "solvent" as used herein refers to a liquid that can dissolve a solid, liquid, or gas. Non-limiting examples of solvents are silicones, organic compounds, water, alcohols, ionic liquids, and supercritical fluids. The term "substantially" as used herein refers to a majority of, or mostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. The term "substantially free of" as used herein can mean having none or having a trivial amount of, such that the amount of material present does not affect the material properties of the composition including the material, such that the composition is about 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to, or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less. The term "substantially free of" can mean having a trivial amount of, such that a composition is about 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to, or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less, or about 0 wt%. The term "substituted" as used herein in conjunction with a molecule or an organic - 24 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) group as defined herein refers to the state in which one or more hydrogen atoms contained therein are replaced by one or more non-hydrogen atoms. The term "functional group" or "substituent" as used herein refers to a group that can be or is substituted onto a molecule or onto an organic group. Examples of substituents or functional groups include, but are not limited to, a halogen (e.g., F, Cl, Br, and I); an oxygen atom in groups such as hydroxy groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboxylate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxyamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups. Non-limiting examples of substituents that can be bonded to a substituted carbon (or other) atom include F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO, NO2, ONO2, azido, CF3, OCF3, R, O (oxo), S (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2)0- 2N(R)C(O)R, (CH2)0-2N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, and C(=NOR)R, wherein R can be hydrogen or a carbon-based moiety; for example, R can be hydrogen, (C1- C100)hydrocarbyl, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl; or wherein two R groups bonded to a nitrogen atom or to adjacent nitrogen atoms can together with the nitrogen atom or atoms form a heterocyclyl. A "therapeutic" treatment is a treatment administered to a subject who exhibits signs of pathology, for the purpose of diminishing or eliminating those signs. As used herein, the term "treatment" or "treating" is defined as the application or administration of a therapeutic agent, i.e., a compound or compounds as described herein (alone or in combination with another pharmaceutical agent), to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell line from a patient (e.g., for diagnosis or ex vivo applications), who has a condition contemplated herein or a symptom of a condition contemplated herein, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect a condition contemplated herein, or the symptoms of a condition contemplated herein. Such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics. In certain embodiments, each occurrence of optionally substituted alkyl, optionally - 25 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) substituted alkylenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl is independently optionally substituted with at least one selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, C2-C8 heteroaryl, halogen, ORa, N(Ra)(Ra), SRa, SSRa, NO2, CN, C(=O)Ra, C(=O)ORa, C(=O)N(Ra)(Ra), C(=NRa)N(Ra)(Ra), N(Ra)C(=O)Ra, N(Ra)C(=O)ORa, N(Ra)C(=O)N(Ra)(Ra), S(=O)ORa, S(=O)Ra, S(=O)2ORa, S(=O)2N(Ra)(Ra), and S(=O)2Ra, wherein each C1-C6 alkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, or C2-C8 heteroaryl is optionally substituted with one to three independently selected Rb; In certain embodiments, each occurrence of Ra is independently selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C2-C8 heteroaryl, C6-C10 aryl, halogen, CN, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)(C1-C6 alkyl), OH, O(C1-C6 alkyl), C(=O)OH, C(=O)O(C1-C6 alkyl), C(=O)NH2, C(=O)NH(C1-C6 alkyl), C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), S(=O)2OH, and S(=O)2NH2, wherein each alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, and aryl in Ra is independently optionally substituted with at least one selected from the group consisting of C1-C6 alkyl, halogen, CN, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)(C1-C6 alkyl), OH, O(C1-C6 alkyl), C(=O)OH, C(=O)O(C1- C6 alkyl), C(=O)NH2, C(=O)NH(C1-C6 alkyl), C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), S(=O)2OH, and S(=O)2NH2. In certain embodiments, each occurrence of Ra is independently selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, C2-C8 heteroaryl, halogen, ORb, N(Rb)(Rb), SRb, SSRb, NO2, CN, C(=O)Rb, C(=O)ORb, C(=O)N(Rb)(Rb), C(=NRb)N(Rb)(Rb), N(Rb)C(=O)Rb, N(Rb)C(=O)ORb, N(Rb)C(=O)N(Rb)(Rb), S(=O)ORb, S(=O)Rb, S(=O)2ORb, S(=O)2N(Rb)(Rb), and S(=O)2Rb, wherein each C1-C6 alkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, or C2-C8 heteroaryl in Ra is optionally substituted with one to three independently selected Rb. In certain embodiments, each occurrence of Rb is independently selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C2-C8 heteroaryl, C6-C10 aryl, halogen, CN, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)(C1-C6 alkyl), OH, O(C1-C6 alkyl), C(=O)OH, C(=O)O(C1-C6 alkyl), C(=O)NH2, C(=O)NH(C1-C6 alkyl), C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), S(=O)2OH, and S(=O)2NH2, wherein each alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, and aryl in Rb is independently optionally substituted with at least one selected from the group consisting of C1-C6 alkyl, halogen, CN, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)(C1-C6 alkyl), OH, O(C1-C6 alkyl), C(=O)OH, - 26 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) C(=O)O(C1-C6 alkyl), C(=O)NH2, C(=O)NH(C1-C6 alkyl), C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), S(=O)2OH, and S(=O)2NH2. In certain embodiments, each occurrence of Rb is independently selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, C2-C8 heteroaryl, halogen, ORc, N(Rc)(Rc), SRc, SSRc, NO2, CN, C(=O)Rc, C(=O)ORc, C(=O)N(Rc)(Rc), C(=NRc)N(Rc)(Rc), N(Rc)C(=O)Rc, N(Rc)C(=O)ORc, N(Rc)C(=O)N(Rc)(Rc), S(=O)ORc, S(=O)Rc, S(=O)2ORc, S(=O)2N(Rc)(Rc), and S(=O)2Rc, wherein each C1-C6 alkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, or C2-C8 heteroaryl in Rb is optionally substituted with one to three independently selected Rc. In certain embodiments, each occurrence of Rc is independently selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C2-C8 heteroaryl, C6-C10 aryl, halogen, CN, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)(C1-C6 alkyl), OH, O(C1-C6 alkyl), C(=O)OH, C(=O)O(C1-C6 alkyl), C(=O)NH2, C(=O)NH(C1-C6 alkyl), C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), S(=O)2OH, and S(=O)2NH2, wherein each alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, and aryl in Rc is independently optionally substituted with at least one selected from the group consisting of C1-C6 alkyl, halogen, CN, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)(C1-C6 alkyl), OH, O(C1-C6 alkyl), C(=O)OH, C(=O)O(C1- C6 alkyl), C(=O)NH2, C(=O)NH(C1-C6 alkyl), C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), S(=O)2OH, and S(=O)2NH2. In certain embodiments, each occurrence of Rc is independently selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, C2-C8 heteroaryl, halogen, ORd, N(Rd)(Rd), SRd, SSRd, NO2, CN, C(=O)Rd, C(=O)ORd, C(=O)N(Rd)(Rd), C(=NRd)N(Rd)(Rd), N(Rd)C(=O)Rd, N(Rd)C(=O)ORd, N(Rd)C(=O)N(Rd)(Rd), S(=O)ORd, S(=O)Rd, S(=O)2ORd, S(=O)2N(Rd)(Rd), and S(=O)2Rd, wherein each C1-C6 alkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, or C2-C8 heteroaryl in Rc is optionally substituted with one to three independently selected Rd. In certain embodiments, each occurrence of Rd is independently selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C2-C8 heteroaryl, C6-C10 aryl, halogen, CN, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)(C1-C6 alkyl), OH, O(C1-C6 alkyl), C(=O)OH, C(=O)O(C1-C6 alkyl), C(=O)NH2, C(=O)NH(C1-C6 alkyl), C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), S(=O)2OH, and S(=O)2NH2, wherein each alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, and aryl in Rd is independently optionally substituted with at least one selected from the group consisting of C1-C6 alkyl, halogen, CN, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)(C1-C6 alkyl), OH, O(C1-C6 alkyl), C(=O)OH, - 27 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) C(=O)O(C1-C6 alkyl), C(=O)NH2, C(=O)NH(C1-C6 alkyl), C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), S(=O)2OH, and S(=O)2NH2. In certain embodiments, each occurrence of Rd is independently selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, C2-C8 heteroaryl, halogen, ORe, N(Re)(Re), SRe, SSRe, NO2, CN, C(=O)Re, C(=O)ORe, C(=O)N(Re)(Re), C(=NRe)N(Re)(Re), N(Re)C(=O)Re, N(Re)C(=O)ORe, N(Re)C(=O)N(Re)(Re), S(=O)ORe, S(=O)Re, S(=O)2ORe, S(=O)2N(Re)(Re), and S(=O)2Re, wherein each C1-C6 alkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, or C2-C8 heteroaryl in Rd is optionally substituted with one to three independently selected Re. In certain embodiments, each occurrence of Re is independently selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C2-C8 heteroaryl, C6-C10 aryl, halogen, CN, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)(C1-C6 alkyl), OH, O(C1-C6 alkyl), C(=O)OH, C(=O)O(C1-C6 alkyl), C(=O)NH2, C(=O)NH(C1-C6 alkyl), C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), S(=O)2OH, and S(=O)2NH2, wherein each alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, and aryl in Re is independently optionally substituted with at least one selected from the group consisting of C1-C6 alkyl, halogen, CN, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)(C1-C6 alkyl), OH, O(C1-C6 alkyl), C(=O)OH, C(=O)O(C1- C6 alkyl), C(=O)NH2, C(=O)NH(C1-C6 alkyl), C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), S(=O)2OH, and S(=O)2NH2. In certain embodiments, each occurrence of Re is independently selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, C2-C8 heteroaryl, halogen, ORf, N(Rf)(Rf), SRf, SSRf, NO2, CN, C(=O)Rf, C(=O)ORf, C(=O)N(Rf)(Rf), C(=NRf)N(Rf)(Rf), N(Rf)C(=O)Rf, N(Rf)C(=O)ORf, N(Rf)C(=O)N(Rf)(Rf), S(=O)ORf, S(=O)Rf, S(=O)2ORf, S(=O)2N(Rf)(Rf), and S(=O)2Rf, wherein each C1-C6 alkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, or C2-C8 heteroaryl in Re is optionally substituted with one to three independently selected Rf. In certain embodiments, each occurrence of Rf is independently selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C2-C8 heteroaryl, C6-C10 aryl, halogen, CN, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)(C1-C6 alkyl), OH, O(C1-C6 alkyl), C(=O)OH, C(=O)O(C1-C6 alkyl), C(=O)NH2, C(=O)NH(C1-C6 alkyl), C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), S(=O)2OH, and S(=O)2NH2, wherein each alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, and aryl in Rf is independently optionally substituted with at least one selected from the group consisting of C1-C6 alkyl, halogen, CN, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)(C1-C6 alkyl), OH, O(C1-C6 alkyl), C(=O)OH, C(=O)O(C1- - 28 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) C6 alkyl), C(=O)NH2, C(=O)NH(C1-C6 alkyl), C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), S(=O)2OH, and S(=O)2NH2. Compounds and Compositions In one aspect, the disclosure provides a compound of Formula (I), or a salt, solvate, stereoisomer, or isotopologue thereof: , wherein: R1 is selected from the substituted C6-C10 aryl and optionally substituted C2-C8 heteroaryl; R2a, R2b, R2c, R2d, R2e, R2f, R2g, R2h, R2i, R2j, R2k, and R2l, if present, are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 heteroalkyl, halogen, CN, NO2, ORA, N(RA)(RB), C(=O)ORA, and C(=O)N(RA)(RB), wherein two geminal substituents selected from R2a, R2b, R2c, R2d, R2e, R2f, R2g, R2h, R2i, R2j, R2k, and R2l can combine with the carbon atom to which they are bound to form C(=O); and wherein one of R2b and R2c is R3; R3 is optionally substituted C6-C10 aryl; L1 is selected from the group consisting of a bond and -C(R2g)(R2h)-; L2 is selected from the group consisting of a bond and -C(R2i)(R2j)-; X1 is selected from the group consisting of -N(R4)-, -O-, and -C(R2k)(R2l)-; R4, if present, is selected from the group consisting of H, optionally substituted C1-C6 alkyl, C(=O)RA, C(=O)ORA, C(=O)N(RA)(RB), C(=NRA)N(RB)(RC), optionally substituted C6-C10 aryl, and optionally substituted C2-C8 heteroaryl; and each occurrence of RA, RB, and RC, if present, is selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 heteroalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C6-C10 aryl, and optionally substituted C2-C8 heteroaryl. - 29 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) In certain embodiments, the compound of Formula (I) is a compound of Formula (Ia): of is a compound of certain embodiments, the compound of Formula (I) is a compound of In certain embodiments, the compound of Formula (I) is a compound of In certain embodiments, the compound of Formula (I) is a compound of Formula (If): (If). In certain embodiments, the compound of Formula (I) is a compound of Formula (Ia- certain embodiments, the compound of Formula (I) is a compound of Formula certain embodiments, the compound of Formula (I) - 30 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) is a compound of Formula In certain embodiments, the compound of Formula (I) is a compound of In certain embodiments, the compound of Formula (I) is a compound of 1). In certain embodiments, the compound of Formula (I) is a : certain embodiments, the compound of Formula (I) is a compound of Formula (Id-1): (Id-1). In certain embodiments, the compound of Formula (I) is a compound of Formula certain embodiments, the compound of Formula (I) is a compound of In certain embodiments, the compound of Formula (I) is a compound of In certain - 31 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) embodiments, the compound of Formula (I) is a compound of Formula (If-1): (If-1). In certain embodiments, the compound of Formula (I) is a compound of Formula (If- , wherein R5a, R5b, R5c, R5d, and R5e are of H, halogen, CN, NO2, ORA, , substituted C6-C10 aryl, and optionally substituted C2-C10 heteroaryl. In certain , wherein R5a, R5b, R5d, and R5e are each independently selected from of H, ha A A B logen, CN, NO2, OR , N(R )(R ), optionally substituted C1-C6 alkyl, optionally substituted C6-C10 aryl, and optionally substituted C2-C10 heteroaryl. In certain embodiments, at least one of R5a, R5b, R5c, R5d, and R5e is phenyl. In certain embodiments, the phenyl in R5a, R5b, R5c, R5d, or R5e is substituted with at least one selected from the group consisting of OH, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkyl, and C1-C6 haloalkyl. In certain embodiments, R5a is H. In certain embodiments, R5a is CH3. In certain embodiments, R5a is Ph. In certain embodiments, R5a . In certain embodiments, R5a . In certain embodiments, R5a . In certain embodiments, R5a is . In certain embodiments, R5a . In certain embodiments, - 32 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) R5b is H. In certain embodiments, R5b is CH3. In certain embodiments, R5b is Ph. In certain embodiments, R5b . In certain embodiments, R5b . In certain embodiments, R5b . In certain embodiments, R5b In certain embodiments, . In certain embodiments, R5c is H. In certain embodiments, R5c is embodiments, R5c is Ph. In certain embodiments, R5c is . In certain embodiments, R5c . In certain embodiments, R5c is . In certain embodiments, R5c . In certain embodiments, certain embodiments, R5d is H. In certain embodiments, R5d is CH3. In certain embodiments, R5d is Ph. In certain embodiments, R5d . In certain embodiments, R5d . In certain embodiments, R5d . In certain embodiments, R5d . In certain embodiments, R5d . In certain embodiments, R5e R5e is CH3. In R5e is Ph. In certain embodiments, R5e . In certain embodiments, . In certain embodiments, R5e . In certain embodiments, R5e is - 33 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) . are each independently H or from the group consisting of Ph, R1 In certain , wherein R6a, R6b, R6c, R6d, and R6e are each independently selected of H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 haloalkyl, optionally substituted C6-C10 aryl, optionally - 34 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) substituted C2-C10 heteroaryl, halogen, CN, NO2, ORA, N(RA)(RB), C(=O)N(RA)(RB), C(=O)ORA, and S(=O)2N(RA)(RB). In certain embodiments, R6a is H. In certain embodiments, R6a is F. In certain embodiments, R6a is Cl. In certain embodiments, R6b is H. In certain embodiments, R6b is F. In certain embodiments, R6b is Cl. In certain embodiments, R6c is H. In certain embodiments, R6c is F. In certain embodiments, R6c is Cl. In certain embodiments, R6d is H. In certain embodiments, R6d is F. In certain embodiments, R6d is Cl. In certain embodiments, R6e is H. In certain embodiments, R6e is F. In certain embodiments, R6e is Cl. In certain embodiments, one of R6a, R6b, R6c, R6d, and R6e is F or Cl. In certain embodiments, R3 . In certain embodiments, R3 In certain embodiments, R3 . In certain embodiments, R3 In certain . In certain is H. 4 In certain embodiments, R is Me. In certain embodiments, R4 is C(=NH)NH2. In certain embodiments, R4 is . In certain . In is selected from the group consisting of: 4-(3-(4-chlorophenyl)-4-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)piperazine-1- carbonyl)-N-methylbenzamide; (S)-4-(3-(4-chlorophenyl)-4-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)piperazine-1- carbonyl)-N-methylbenzamide; (R)-4-(3-(4-chlorophenyl)-4-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)piperazine- 1-carbonyl)-N-methylbenzamide; 2-(4-fluorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-4-methylpiperazine; (S)-2-(4-fluorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-4- methylpiperazine; - 35 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) (R)-2-(4-fluorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-4- methylpiperazine; 2-(4-chlorophenyl)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)piperazine; (S)-2-(4-chlorophenyl)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)piperazine; (R)-2-(4-chlorophenyl)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)piperazine; 3-(4-((2-(4-chlorophenyl)piperazin-1-yl)methyl)pyridin-3-yl)-4- (trifluoromethoxy)phenol; (S)-3-(4-((2-(4-chlorophenyl)piperazin-1-yl)methyl)pyridin-3-yl)-4- (trifluoromethoxy)phenol; (R)-3-(4-((2-(4-chlorophenyl)piperazin-1-yl)methyl)pyridin-3-yl)-4- (trifluoromethoxy)phenol; 2'-((2-(4-chlorophenyl)piperazin-1-yl)methyl)-6-(trifluoromethoxy)-[1,1'-biphenyl]-3- ol; (S)-2'-((2-(4-chlorophenyl)piperazin-1-yl)methyl)-6-(trifluoromethoxy)-[1,1'- biphenyl]-3-ol; (R)-2'-((2-(4-chlorophenyl)piperazin-1-yl)methyl)-6-(trifluoromethoxy)-[1,1'- biphenyl]-3-ol; 2'-((2-(4-fluorophenyl)piperazin-1-yl)methyl)-6-(trifluoromethoxy)-[1,1'-biphenyl]-3- ol; (S)-2'-((2-(4-fluorophenyl)piperazin-1-yl)methyl)-6-(trifluoromethoxy)-[1,1'- biphenyl]-3-ol; (R)-2'-((2-(4-fluorophenyl)piperazin-1-yl)methyl)-6-(trifluoromethoxy)-[1,1'- biphenyl]-3-ol; 2-(4-fluorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; (S)-2-(4-fluorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; (R)-2-(4-fluorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; 2-(4-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; (S)-2-(4-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; (R)-2-(4-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; 2'-((2-(3-chlorophenyl)piperazin-1-yl)methyl)-6-(trifluoromethoxy)-[1,1'-biphenyl]-3- ol; (S)-2'-((2-(3-chlorophenyl)piperazin-1-yl)methyl)-6-(trifluoromethoxy)-[1,1'- biphenyl]-3-ol; (R)-2'-((2-(3-chlorophenyl)piperazin-1-yl)methyl)-6-(trifluoromethoxy)-[1,1'- - 36 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) biphenyl]-3-ol; 2-(4-chlorophenyl)-1-((2'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)methyl)piperazine; (S)-2-(4-chlorophenyl)-1-((2'-(trifluoromethyl)-[1,1'-biphenyl]-2- yl)methyl)piperazine; (R)-2-(4-chlorophenyl)-1-((2'-(trifluoromethyl)-[1,1'-biphenyl]-2- yl)methyl)piperazine; 3-(4-((2-(4-fluorophenyl)-4-methylpiperazin-1-yl)methyl)pyridin-3-yl)-4- (trifluoromethoxy)phenol; (S)-3-(4-((2-(4-fluorophenyl)-4-methylpiperazin-1-yl)methyl)pyridin-3-yl)-4- (trifluoromethoxy)phenol; (R)-3-(4-((2-(4-fluorophenyl)-4-methylpiperazin-1-yl)methyl)pyridin-3-yl)-4- (trifluoromethoxy)phenol; 2'-((2-(4-chlorophenyl)piperazin-1-yl)methyl)-5'-methyl-6-(trifluoromethoxy)-[1,1'- biphenyl]-3-ol; (S)-2'-((2-(4-chlorophenyl)piperazin-1-yl)methyl)-5'-methyl-6-(trifluoromethoxy)- [1,1'-biphenyl]-3-ol; (R)-2'-((2-(4-chlorophenyl)piperazin-1-yl)methyl)-5'-methyl-6-(trifluoromethoxy)- [1,1'-biphenyl]-3-ol; 2'-((2-(4-fluorophenyl)-4-methylpiperazin-1-yl)methyl)-6-(trifluoromethoxy)-[1,1'- biphenyl]-3-ol; (S)-2'-((2-(4-fluorophenyl)-4-methylpiperazin-1-yl)methyl)-6-(trifluoromethoxy)- [1,1'-biphenyl]-3-ol; (R)-2'-((2-(4-fluorophenyl)-4-methylpiperazin-1-yl)methyl)-6-(trifluoromethoxy)- [1,1'-biphenyl]-3-ol; 2-(4-fluorophenyl)-4-methyl-1-((2'-(trifluoromethyl)-[1,1'-biphenyl]-2- yl)methyl)piperazine; (S)-2-(4-fluorophenyl)-4-methyl-1-((2'-(trifluoromethyl)-[1,1'-biphenyl]-2- yl)methyl)piperazine; (R)-2-(4-fluorophenyl)-4-methyl-1-((2'-(trifluoromethyl)-[1,1'-biphenyl]-2- yl)methyl)piperazine; 2-(3-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; (S)-2-(3-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; (R)-2-(3-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; 2-(2-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; - 37 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) (S)-2-(2-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; (R)-2-(2-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; 2'-((2-(4-fluorophenyl)piperazin-1-yl)methyl)-6-(trifluoromethoxy)-[1,1'-biphenyl]-3- ol; (S)-2'-((2-(4-fluorophenyl)piperazin-1-yl)methyl)-6-(trifluoromethoxy)-[1,1'- biphenyl]-3-ol; (R)-2'-((2-(4-fluorophenyl)piperazin-1-yl)methyl)-6-(trifluoromethoxy)-[1,1'- biphenyl]-3-ol; 2-(4-fluorophenyl)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)piperazine; (S)-2-(4-fluorophenyl)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)piperazine; (R)-2-(4-fluorophenyl)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)piperazine; 3-(4-chlorophenyl)-4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine-1- carboximidamide; (S)-3-(4-chlorophenyl)-4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine-1- carboximidamide; (R)-3-(4-chlorophenyl)-4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine-1- carboximidamide; 3-(4-((2-(4-fluorophenyl)piperazin-1-yl)methyl)pyridin-3-yl)-4- (trifluoromethoxy)phenol; (S)-3-(4-((2-(4-fluorophenyl)piperazin-1-yl)methyl)pyridin-3-yl)-4- (trifluoromethoxy)phenol; (R)-3-(4-((2-(4-fluorophenyl)piperazin-1-yl)methyl)pyridin-3-yl)-4- (trifluoromethoxy)phenol; 3-(4-fluorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; (S)-3-(4-fluorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; (R)-3-(4-fluorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; 2-(4-chlorophenyl)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)piperazine; (S)-2-(4-chlorophenyl)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)piperazine; (R)-2-(4-chlorophenyl)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)piperazine; 2-(4-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-4-methylpiperazine; (S)-2-(4-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-4- methylpiperazine; (R)-2-(4-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-4- methylpiperazine; - 38 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) 2-(4-fluorophenyl)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)-4- methylpiperazine; (S)-2-(4-fluorophenyl)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)-4- methylpiperazine; (R)-2-(4-fluorophenyl)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)-4- methylpiperazine; 5-(2-((2-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)quinoline; (S)-5-(2-((2-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)quinoline; (R)-5-(2-((2-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)quinoline; 4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-5-phenylpiperazin-2-one; (S)-4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-5-phenylpiperazin-2-one; (R)-4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-5-phenylpiperazin-2-one; 2-(4-chlorophenyl)-1-((3-phenylpyridin-4-yl)methyl)piperazine; (S)-2-(4-chlorophenyl)-1-((3-phenylpyridin-4-yl)methyl)piperazine; (R)-2-(4-chlorophenyl)-1-((3-phenylpyridin-4-yl)methyl)piperazine; 1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)-2-phenylpiperazine; (S)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)-2-phenylpiperazine; (R)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)-2-phenylpiperazine; 2'-((3-(4-chlorophenyl)morpholino)methyl)-6-(trifluoromethoxy)-[1,1'-biphenyl]-3-ol; (S)-2'-((3-(4-chlorophenyl)morpholino)methyl)-6-(trifluoromethoxy)-[1,1'-biphenyl]- 3-ol; (R)-2'-((3-(4-chlorophenyl)morpholino)methyl)-6-(trifluoromethoxy)-[1,1'-biphenyl]- 3-ol; 3-(4-chlorophenyl)-4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)morpholine; (S)-3-(4-chlorophenyl)-4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)morpholine; (R)-3-(4-chlorophenyl)-4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)morpholine; 3-(4-fluorophenyl)-4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)morpholine; (S)-3-(4-fluorophenyl)-4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)morpholine; (R)-3-(4-fluorophenyl)-4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)morpholine; 2'-((3-(4-chlorophenyl)morpholino)methyl)-5-(trifluoromethoxy)-[1,1'-biphenyl]-2-ol; (S)-2'-((3-(4-chlorophenyl)morpholino)methyl)-5-(trifluoromethoxy)-[1,1'-biphenyl]- 2-ol; (R)-2'-((3-(4-chlorophenyl)morpholino)methyl)-5-(trifluoromethoxy)-[1,1'-biphenyl]- 2-ol; - 39 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) 4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-3-phenylmorpholine; (S)-4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-3-phenylmorpholine; (R)-4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-3-phenylmorpholine; 2-(4-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-4-(pyridin-2- yl)piperazine; (S)-2-(4-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-4-(pyridin-2- yl)piperazine; and (R)-2-(4-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-4-(pyridin-2- yl)piperazine. In another aspect, the disclosure provides a compound of Formula (II), or a salt, solvate, stereoisomer, or isotopologue thereof: , wherein X2 is selected from the group consisting of S, O, and N(R11); X3 is selected from the group consisting of C(R7c) and N; Y1 and Y2 are each independently selected from the group consisting of N and C(R7g); L3 is -[C(R7e)(R7f)]1-3- or a bond; L4 is selected from the group consisting of a bond, -C(=O)-, and -C(R7h)(R7i)-; each occurrence of R7a, R7b, R7c, R7d, R7e, and R7f is each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 heteroalkyl, halogen, CN, NO2, ORD, N(RD)(RE), C(=O)ORD, and C(=O)N(RD)(RE); R8 is optionally substituted C6-C10 aryl; R9 is selected from the group consisting of H, optionally substituted C6-C10 aryl, and optionally substituted C2-C8 heteroaryl; R10a and R10b are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 heteroalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C6-C10 aryl, and optionally substituted C2-C8 heteroaryl, wherein R10a and R10b can combine with the atoms to which they are bound to form an optionally substituted C3-C8 heterocycloalkyl; - 40 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) R11 is selected from the group consisting of H and optionally substituted C1-C6 alkyl; and each occurrence of RD and RE, if present, is selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 heteroalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C6-C10 aryl, and optionally substituted C2-C8 heteroaryl. In certain embodiments, at least one of R7a, R7b, R7c, and R7d is H. In certain embodiments, at least two of R7a, R7b, R7c, and R7d are H. In certain embodiments, at least three of R7a, R7b, R7c, and R7d are H. In certain embodiments, each of R7a, R7b, R7c, and R7d are H. In certain embodiments, R7e is H. In certain embodiments, R7e is CH3. In certain embodiments, R7e is CH2OCH3. In certain embodiments, R7e is . In certain R7e . In R7f is H. In certain embodiments, R7f is CH3. In certain embodiments, R7f is CH2OCH3. In certain embodiments, R7f is . In certain . In R8 is phenyl optionally substituted with at least one halogen. In certain embodiments, R8 is phenyl. In certain embodiments, R8 is 4-chlorophenyl. In certain embodiments, R8 is 4-fluorophenyl. In certain embodiments, L3 is a bond. In certain embodiments, L3 is –(CH2)-. In certain embodiments, L3 is –(CHCH3)-. In certain embodiments, L3 is –[CH(CH2OCH3)]CH2- . In certain embodiments, L3 . In certain embodiments, In certain optionally substituted R9 is optionally substituted indolyl. In certain embodiments, R9 is optionally substituted naphthyl. In certain embodiments, the phenyl is optionally substituted with at least one C1-C6 haloalkyl. In certain embodiments, the haloalkyl is CF3. In certain embodiments, R9 is . In certain embodiments, R9 9 . In certain embodiments, R is - 41 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) . is H. In certain embodiments, the combination of L3-R9 is . In certain embodiments, the combination of L3-R9 is . In certain embodiments, the combination of L3-R9 . In certain embodiments, the combination of L3-R9 . In certain embodiments, the combination of L3-R9 . In certain embodiments, the combination of L3-R9 . In certain embodiments, the combination of L3-R9 In certain embodiments, the In certain embodiments, the certain embodiments, the combination of L3-R9 is certain embodiments, the In certain embodiments, the In certain embodiments, the - 42 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) certain embodiments, the combination of L3-R9 is . In certain embodiments, the combination of L3-R9 . In certain embodiments, the combination of L3-R9 . In certain embodiments, the certain embodiments, the combination of L3-R9 is certain embodiments, the In certain embodiments, the combination of L3-R9 . In certain embodiments, R10a and selected from the group consisting of H, C1-C6 alkyl, and optionally substituted C3-C6 cycloalkyl. In certain embodiments, R10a is H. In certain embodiments, R10a is CH3. In certain is In - 43 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) certain embodiments, R10a and R10b are both CH3. In certain embodiments, the compound is selected from the group consisting of: 2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(cyclopropyl(phenyl)methyl)-N-methyl-1H- benzo[d]imidazole-5-carboxamide; (R)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(cyclopropyl(phenyl)methyl)-N-methyl- 1H-benzo[d]imidazole-5-carboxamide; (S)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(cyclopropyl(phenyl)methyl)-N-methyl-1H- benzo[d]imidazole-5-carboxamide; 1-benzyl-N-methyl-2-(4-phenylthiazol-2-yl)-1H-benzo[d]imidazole-5-carboxamide; 2-(4-(4-chlorophenyl)thiazol-2-yl)-N-methyl-1-(1-(4-(trifluoromethyl)phenyl)ethyl)- 1H-benzo[d]imidazole-5-carboxamide; (R)-2-(4-(4-chlorophenyl)thiazol-2-yl)-N-methyl-1-(1-(4- (trifluoromethyl)phenyl)ethyl)-1H-benzo[d]imidazole-5-carboxamide; (S)-2-(4-(4-chlorophenyl)thiazol-2-yl)-N-methyl-1-(1-(4- (trifluoromethyl)phenyl)ethyl)-1H-benzo[d]imidazole-5-carboxamide; 2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-methoxy-1-phenylethyl)-N-methyl-1H- benzo[d]imidazole-5-carboxamide; (R)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-methoxy-1-phenylethyl)-N-methyl-1H- benzo[d]imidazole-5-carboxamide; (S)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-methoxy-1-phenylethyl)-N-methyl-1H- benzo[d]imidazole-5-carboxamide; N-methyl-2-(4-phenylthiazol-2-yl)-1H-benzo[d]imidazole-5-carboxamide; 2-(4-(4-chlorophenyl)thiazol-2-yl)-N-methyl-1H-benzo[d]imidazole-5-carboxamide; 1-benzyl-2-(4-(4-chlorophenyl)thiazol-2-yl)-N-methyl-1H-benzo[d]imidazole-5- carboxamide; 1-((1H-indol-4-yl)methyl)-2-(4-(4-chlorophenyl)thiazol-2-yl)-N-methyl-1H- benzo[d]imidazole-5-carboxamide; 2-(4-(4-chlorophenyl)thiazol-2-yl)-N-methyl-1-(1-(naphthalen-2-yl)ethyl)-1H- benzo[d]imidazole-5-carboxamide; (R)-2-(4-(4-chlorophenyl)thiazol-2-yl)-N-methyl-1-(1-(naphthalen-2-yl)ethyl)-1H- benzo[d]imidazole-5-carboxamide; (S)-2-(4-(4-chlorophenyl)thiazol-2-yl)-N-methyl-1-(1-(naphthalen-2-yl)ethyl)-1H- benzo[d]imidazole-5-carboxamide; 2-(4-(4-chlorophenyl)thiazol-2-yl)-N-methyl-1-(1-(4-(trifluoromethyl)phenyl)ethyl)- - 44 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) 1H-benzo[d]imidazole-5-carboxamide; (R)-2-(4-(4-chlorophenyl)thiazol-2-yl)-N-methyl-1-(1-(4- (trifluoromethyl)phenyl)ethyl)-1H-benzo[d]imidazole-5-carboxamide; (S)-2-(4-(4-chlorophenyl)thiazol-2-yl)-N-methyl-1-(1-(4- (trifluoromethyl)phenyl)ethyl)-1H-benzo[d]imidazole-5-carboxamide; 2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-methoxy-1-phenylethyl)-N-methyl-1H- benzo[d]imidazole-5-carboxamide; (R)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-methoxy-1-phenylethyl)-N-methyl-1H- benzo[d]imidazole-5-carboxamide; (S)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-methoxy-1-phenylethyl)-N-methyl-1H- benzo[d]imidazole-5-carboxamide; 1-(cyclopropyl(phenyl)methyl)-2-(4-(4-fluorophenyl)thiazol-2-yl)-N-methyl-1H- benzo[d]imidazole-5-carboxamide; (R)-1-(cyclopropyl(phenyl)methyl)-2-(4-(4-fluorophenyl)thiazol-2-yl)-N-methyl-1H- benzo[d]imidazole-5-carboxamide; (S)-1-(cyclopropyl(phenyl)methyl)-2-(4-(4-fluorophenyl)thiazol-2-yl)-N-methyl-1H- benzo[d]imidazole-5-carboxamide; 2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(cyclopropyl(phenyl)methyl)-N,N-dimethyl-1H- benzo[d]imidazole-5-carboxamide; (R)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(cyclopropyl(phenyl)methyl)-N,N-dimethyl- 1H-benzo[d]imidazole-5-carboxamide; (S)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(cyclopropyl(phenyl)methyl)-N,N-dimethyl- 1H-benzo[d]imidazole-5-carboxamide; 2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(cyclopropyl(phenyl)methyl)-1H- benzo[d]imidazole-5-carboxamide; (R)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(cyclopropyl(phenyl)methyl)-1H- benzo[d]imidazole-5-carboxamide; (S)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(cyclopropyl(phenyl)methyl)-1H- benzo[d]imidazole-5-carboxamide; 2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-methoxy-1-phenylethyl)-1H- benzo[d]imidazole-5-carboxamide; (R)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-methoxy-1-phenylethyl)-1H- benzo[d]imidazole-5-carboxamide; (S)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-methoxy-1-phenylethyl)-1H- - 45 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) benzo[d]imidazole-5-carboxamide; 2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-methoxy-1-phenylethyl)-N,N-dimethyl-1H- benzo[d]imidazole-5-carboxamide; (R)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-methoxy-1-phenylethyl)-N,N-dimethyl- 1H-benzo[d]imidazole-5-carboxamide; (S)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-methoxy-1-phenylethyl)-N,N-dimethyl- 1H-benzo[d]imidazole-5-carboxamide; 2-(4-(4-chlorophenyl)thiazol-2-yl)-3-(cyclopropyl(phenyl)methyl)-3H-imidazo[4,5- b]pyridine-6-carboxamide; (R)-2-(4-(4-chlorophenyl)thiazol-2-yl)-3-(cyclopropyl(phenyl)methyl)-3H- imidazo[4,5-b]pyridine-6-carboxamide; and (S)-2-(4-(4-chlorophenyl)thiazol-2-yl)-3-(cyclopropyl(phenyl)methyl)-3H- imidazo[4,5-b]pyridine-6-carboxamide. Table 1. Exemplary compounds of the disclosure. Cmpd Structure Name 4-(3-(4-chlorophenyl)-4-((3-(2- CDD- isopropylphenyl)pyridin-4- 1938 yl)methyl)piperazine-1-carbonyl)-N- methylbenzamide (R)-2-(4-fluorophenyl)-1-’(2'-isopropyl- CDD- [’,1'-biphenyl]-2-yl)methyl)-4- 3003 methylpiperazine - 46 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) (R)-2-(4-chlorophenyl)-1-((3-(2- CDD- isopropylphenylpyridinedin-4- 2750 yl)methyl)piperazine (R)-3-(4-((2-(4-chlorophenyl)piperazin- CDD- 1-yl)methylpyridinedin-3-yl)-4- 2847 (trifluoromethoxy)phenol (R’-2'-((2-(4-chlorophenyl)piperazin-1- CDD- yl)methyl)-6-(trifluoromethoxy)-[’,1'- 2902 biphenyl]-3-ol (R’-2'-((2-(4-fluorophenyl)piperazin-1- CDD- yl)methyl)-6-(trifluoromethoxy)-[’,1'- 3019 biphenyl]-3-ol CDD- (R)-2-(4-fluorophenyl)-1-’(2'-isopropyl- 3002 [’,1'-biphenyl]-2-yl)methyl)piperazine - 47 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) (R)-2-(4-chlorophenyl)-1-’(2'- CDD- isopropyl-[’,1'-biphenyl]-2- 2901 yl)methyl)piperazine (R’-2'-((2-(3-chlorophenyl)piperazin-1- CDD- yl)methyl)-6-(trifluoromethoxy)-[’,1'- 3287 biphenyl]-3-ol (R)-2-(4-chlorophenyl)-1-’(2'- CDD- (trifluoromethyl)-[’,1'-biphenyl]-2- 3062 yl)methyl)piperazine (R)-3-(4-((2-(4-fluorophenyl)-4- CDD- methylpiperazin-1- 3350 yl)methylpyridinedin-3-yl)-4- (trifluoromethoxy)phenol (R’-2'-((2-(4-chlorophenyl)piperazin-1- CDD- yl)methyl’-5'-methyl-6- 2918 (trifluoromethoxy)-[’,1'-biphenyl]-3-ol - 48 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) (R’-2'-((2-(4-fluorophenyl)-4- CDD- methylpiperazin-1-yl)methyl)-6- 3368 (trifluoromethoxy)-[’,1'-biphenyl]-3-ol (R)-2-(4-fluorophenyl)-4-methyl-1-’(2'- CDD- (trifluoromethyl)-[’,1'-biphenyl]-2- 3384 yl)methyl)piperazine (R)-2-(3-chlorophenyl)-1-’(2'- CDD- isopropyl-[’,1'-biphenyl]-2- 3286 yl)methyl)piperazine (R)-2-(2-chlorophenyl)-1-’(2'- CDD- isopropyl-[’,1'-biphenyl]-2- 3196 yl)methyl)piperazine (R’-2'-((2-(4-fluorophenyl)piperazin-1- CDD- yl)methyl)-6-(trifluoromethoxy)-[’,1'- 3227 biphenyl]-3-ol - 49 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) (R)-2-(4-fluorophenyl)-1-((3-(2- CDD- isopropylphenylpyridinedin-4- 3228 yl)methyl)piperazine (R)-4-(3-(4-chlorophenyl)-4-((3-(2- CDD- isopropylphenylpyridinedin-4- 2778 yl)methyl)piperazine-1-carbonyl)-N- methylbenzamide (R)-3-(4-chlorophenyl)-4-’(2'- CDD- isopropyl-[’,1'-biphenyl]-2- 3295 yl)methyl)piperazine-1- carboximidamide (R)-3-(4-((2-(4-fluorophenyl)piperazin- CDD- 1-yl)methylpyridinedin-3-yl)-4- 3227 (trifluoromethoxy)phenol - 50 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) CDD- (R)-3-(4-fluorophenyl)-1-’(2'-isopropyl- 3260 [’,1'-biphenyl]-2-yl)methyl)piperazine 2-(4-chlorophenyl)-1-((3-(2- CDD- isopropylphenylpyridinedin-4- 2723 yl)methyl)piperazine (S)-2-(4-chlorophenyl)-1-((3-(2- CDD- isopropylphenylpyridinedin-4- 2749 yl)methyl)piperazine (S)-4-(3-(4-chlorophenyl)-4-((3-(2- CDD- isopropylphenylpyridinedin-4- 2748 yl)methyl)piperazine-1-carbonyl)-N- methylbenzamide - 51 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) (R)-2-(4-chlorophenyl)-1-’(2'- CDD- isopropyl-[’,1'-biphenyl]-2-yl)methyl)- 3035 4-methylpiperazine (R)-2-(4-fluorophenyl)-1-((3-(2- CDD- isopropylphenylpyridinedin-4- 3337 yl)methyl)-4-methylpiperazine CDD- (R)-5-(2-((2-(4-fluorophenyl)piperazin- 3263 1-yl)methyl)phenyl)quinoline CDD- (R)-4-’(2'-isopropyl-[’,1'-biphenyl]-2- 3149 yl)methyl)-5-phenylpiperazin-2-one CDD- (R)-2-(4-chlorophenyl)-1-((3- 2889 phenylpyridin-4-yl)methyl)piperazine - 52 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) CDD- (R)-1-((3-(2-isopropylphenylyridinedin- 2835 4-yl)methyl)-2-phenylpiperazine (R’-2'-((3-(4- CDD- chlorophenyl)morpholino)methyl)-6- 3212 (trifluoromethoxy)-[’,1'-biphenyl]-3-ol (R)-3-(4-chlorophenyl)-4-’(2'- CDD- isopropyl-[’,1'-biphenyl]-2- 3213 yl)methyl)morpholine CDD- (R)-3-(4-fluorophenyl)-4-’(2'-isopropyl- 3239 [’,1'-biphenyl]-2-yl)methyl)morpholine (R’-2'-((3-(4- CDD- chlorophenyl)morpholino)methyl)-5- 3240 (trifluoromethoxy)-[’,1'-biphenyl]-2-ol - 53 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) O N CDD- (R)-4-’(2'-isopropyl-[’,1'-biphenyl]-2- 3084 yl)methyl)-3-phenylmorpholine N CDD- (S)-2-(4-chlorophenyl)-1-’(2'-isopropyl- Cl 3083 [’,1'-biphenyl]-2-yl)methyl)piperidine (R)-2-(4-chlorophenyl)-1-’(2'- CDD- isopropyl-[’,1'-biphenyl]-2- 3124 yl)methyl)pyrrolidine (R)-2-(4-chlorophenyl)-1-’(2'- CDD- isopropyl-[’,1'-biphenyl]-2-yl)methyl)- 3259 54yridinedin-2-yl)piperazine (R)-2-(4-(4-chlorophenyl)thiazol-2-yl)- N-methyl-1-(1-(4- CDD- (trifluoromethyl)phenyl)ethyl)-1H- 3357 benzo[d]imidazole-5-carboxamide 1-benzyl-N-methyl-2-(4-phenylthiazol- CDD- 2-yl)-1H-benzo[d]imidazole-5- 1794 carboxamide - 54 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) (S)-2-(4-(4-chlorophenyl)thiazol-2-yl)- 1-(cyclopropyl(phenyl)methyl)-N- CDD- methyl-1H-benzo[d]imidazole-5- 3356 carboxamide 2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2- CDD- methoxy-1-phenylethyl)-N-methyl-1H- 3366 benzo[d]imidazole-5-carboxamide CDD- N-methyl-2-(4-phenylthiazol-2-yl)-1H- 2797 benzo[d]imidazole-5-carboxamide 2-(4-(4-chlorophenyl)thiazol-2-yl)-N- CDD- methyl-1H-benzo[d]imidazole-5- 2832 carboxamide 1-benzyl-2-(4-(4-chlorophenyl)thiazol- CDD- 2-yl)-N-methyl-1H-benzo[d]imidazole- 2833 5-carboxamide 1-((1H-indol-4-yl)methyl)-2-(4-(4- CDD- chlorophenyl)thiazol-2-yl)-N-methyl- 3359 1H-benzo[d]imidazole-5-carboxamide (S)-2-(4-(4-chlorophenyl)thiazol-2-yl)- CDD- N-methyl-1-(1-(naphthalen-2-yl)ethyl)- 3367 1H-benzo[d]imidazole-5-carboxamide - 55 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) (R)-2-(4-(4-chlorophenyl)thiazol-2-yl)- CDD- N-methyl-1-(1-(4- 3357 (trifluoromethyl)phenyl)ethyl)-1H- benzo[d]imidazole-5-carboxamide 2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2- CDD- methoxy-1-phenylethyl)-N-methyl-1H- 3367 benzo[d]imidazole-5-carboxamide (S)-1-(cyclopropyl(phenyl)methyl)-2- CDD- (4-(4-fluorophenyl)thiazol-2-yl)-N- 3682 methyl-1H-benzo[d]imidazole-5- carboxamide (S)-2-(4-(4-chlorophenyl)thiazol-2-yl)- CDD- 1-(cyclopropyl(phenyl)methyl)-N,N- 3633 dimethyl-1H-benzo[d]imidazole-5- carboxamide (S)-2-(4-(4-chlorophenyl)thiazol-2-yl)- CDD- 1-(cyclopropyl(phenyl)methyl)-1H- 3634 benzo[d]imidazole-5-carboxamide 2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2- CDD- methoxy-1-phenylethyl)-1H- 3636 benzo[d]imidazole-5-carboxamide - 56 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) 2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2- CDD- methoxy-1-phenylethyl)-N,N-dimethyl- 3635 1H-benzo[d]imidazole-5-carboxamide (S)-2-(4-(4-chlorophenyl)thiazol-2-yl)- CDD- 3-(cyclopropyl(phenyl)methyl)-3H- 3638 imidazo[4,5-b]pyridine-6-carboxamide In another aspect, the disclosure provides a pharmaceutical composition comprising at least one compound of the disclosure and a pharmaceutically acceptable carrier or excipient. In certain embodiments, at least one additional agent suitable for treating, preventing, and/or ameliorating a bacterial infection. In certain embodiments, the at least one additional agent suitable for treating, preventing, and/or ameliorating a bacterial infection is selected from the group consisting of a polymyxin, aminoglycoside, β-lactam (e.g., penicillin, cephalosporin, or carbapenem), monobactam, fluoroquinolone, sulfonamide, tetracycline, and macrolide. In certain embodiments, the additional agent suitable for treating, preventing, and/or ameliorating a bacterial infection is at least one selected from the group consisting of colistin (polymyxin E), polymyxin B, amikacin, ampicillin, amoxicillin, aminoglycoside, azithromycin, aztreonam, carbapenem, cefepime, cefiderocol, cefotaxime, ceftriaxone, ceftaroline, ceftazidime, ceftobiprole, ceftolozane, ciprofloxacin, clindamycin, dalbavancin, daptomycin, doxycycline, ertapenem, fluoroquinolone, gentamicin, imipenem, levofloxacin, linezolid, meropenem, minocycline, mupirocin, oritavancin, piperacillin, streptogramin, sulbactam, tedizolid, telavancin, tigecycline, ticarcillin, tobramycin, trimethoprim/sulfamethoxazole, and vancomycin. The compositions containing the compound(s) described herein include a pharmaceutical composition comprising at least one compound as described herein and at least one pharmaceutically acceptable carrier. In certain embodiments, the composition is formulated for an administration route such as oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal, intravesical, intrapulmonary, intraduodenal, - 57 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration. In some aspects, provided herein is a pharmaceutical composition comprising a compound provided herein and further comprising a pharmaceutically acceptable excipient. Preparation of Compounds Compounds described herein can be prepared by the general schemes described herein, using the synthetic method known by those skilled in the art. The following examples illustrate non-limiting embodiments of the compound(s) described herein and their preparation. The compounds described herein can possess one or more stereocenters, and each stereocenter can exist independently in either the (R) or (S) configuration. In certain embodiments, compounds described herein are present in optically active or racemic forms. It is to be understood that the compounds described herein encompass racemic, optically-active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein. Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In certain embodiments, a mixture of one or more isomer is utilized as the therapeutic compound described herein. In other embodiments, compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis and/or separation of a mixture of enantiomers and/ or diastereomers. Resolution of compounds and isomers thereof is achieved by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography. The methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), solvates, amorphous phases, and/or pharmaceutically acceptable salts of compounds having the structure of any compound(s) described herein, as well as metabolites and active metabolites of these compounds having the same type of activity. Solvates include water, ether (e.g., tetrahydrofuran, methyl tert-butyl ether) or alcohol (e.g., ethanol) solvates, acetates and the like. In certain embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, and ethanol. In other embodiments, the - 58 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) compounds described herein exist in unsolvated form. In certain embodiments, the compound(s) described herein can exist as tautomers. All tautomers are included within the scope of the compounds presented herein. In certain embodiments, compounds described herein are prepared as prodrugs. A “prodrug” refers to an agent that is converted into the parent drug in vivo. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In other embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound. In certain embodiments, sites on, for example, the aromatic ring portion of compound(s) described herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the aromatic ring structures may reduce, minimize or eliminate this metabolic pathway. In certain embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a deuterium, a halogen, or an alkyl group. Compounds described herein also include isotopically-labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include and are not limited to 2H, 3H, 11C, 13C, 14C, 36Cl, 18F, 123I, 125I, 13N, 15N, 15O, 17O, 18O, 32P, and 35S. In certain embodiments, isotopically-labeled compounds are useful in drug and/or substrate tissue distribution studies. In other embodiments, substitution with heavier isotopes such as deuterium affords greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements). In yet other embodiments, substitution with positron emitting isotopes, such as 11C, 18F, 15O and 13N, is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. In certain embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. The compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein and as described, for example, in Fieser & Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley - 59 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4th Ed., (Wiley 1992); Carey & Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000, 2001), and Green & Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compound as described herein are modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formula as provided herein. Compounds described herein are synthesized using any suitable procedures starting from compounds that are available from commercial sources, or are prepared using procedures described herein. In certain embodiments, reactive functional groups, such as hydroxyl, amino, imino, thio or carboxy groups, are protected in order to avoid their unwanted participation in reactions. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. In other embodiments, each protective group is removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal. In certain embodiments, protective groups are removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and/or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and are used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic acid and hydroxy reactive moieties are blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl, in the presence of amines that are blocked with acid labile groups, such as t-butyl carbamate, or with carbamates that are both acid and base stable but hydrolytically removable. In certain embodiments, carboxylic acid and hydroxy reactive moieties are blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids are blocked with base labile groups such as Fmoc. Carboxylic acid reactive moieties are protected by conversion to simple ester compounds as exemplified herein, which include conversion to alkyl esters, or are blocked with oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while co- - 60 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) existing amino groups are blocked with fluoride labile silyl carbamates. Allyl blocking groups are useful in the presence of acid- and base- protecting groups since the former are stable and are subsequently removed by metal or pi-acid catalysts. For example, an allyl-blocked carboxylic acid is deprotected with a palladium-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate is attached. As long as the residue is attached to the resin, that functional group is blocked and does not react. Once released from the resin, the functional group is available to react. Typically blocking/protecting groups may be selected from allyl, benzyl (Bn), benzyloxycarbonyl (Cbz), allyloxycarbonyl (Alloc), methyl, ethyl, t-butyl, t- butyldimethylsilyl (TBDMS), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), t-butyloxycarbonyl (Boc), para-methoxybenzyl (PMB), triphenylmethyl (trityl), acetyl, and fluorenylmethoxycarbonyl (FMOC). Other protecting groups, plus a detailed description of techniques applicable to the creation of protecting groups and their removal are described in Greene & Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for such disclosure. Methods In another aspect, the disclosure provides a method of treating, preventing, and/or ameliorating a bacterial infection in a subject. In certain embodiments, the method comprises administering to the subject at least one compound of the disclosure or the pharmaceutical composition of the disclosure. In certain embodiments, the method comprises administering to the subject at least one polymyxin antibiotic, or an analogue or derivative thereof. In another aspect, the disclosure provides a method of sensitizing a bacterial colony to at least one antibiotic polypeptide. In certain embodiments, the method comprises contacting the bacterial colony with at least one compound of the disclosure or the pharmaceutical composition of the disclosure. In certain embodiments, antibiotic polypeptide is colistin (polymyxin E). In certain embodiments, polymyxin antibiotic is polymyxin B. In certain embodiments, the antibiotic polypeptide is a defensin. In certain embodiments, the antibiotic polypeptide comprises about 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, 200, 300, or 500 amino acids. In certain embodiments, the antibiotic polypeptide is a defensin. In certain embodiments, the - 61 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) antibiotic polypeptide has a charge of about +1, +2, +3, +4, +5, +10, +15, +20, +25, or +30 at a pH of about 7.4. In certain embodiments, the bacterial infection or bacterial colony comprises a bacterial species selected from the group consisting of: Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus lugdenensis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus saprophyticus, Staphylococcus simulans, Staphylococcus warnerii, Staphylococcus capitis, Staphylococcus caprae, Staphylococcus pettenkoferi, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus pneumoniae, Group C streptococci, Streptococcus constellatus, Enterococcus faecalis, Enterococcus faecium, Corynebacterium jeikeium, Lactobacillus acidophilus, Listeria monocytogenes, Escherichia coli, Klebsiella pneumoniae, Klebsiella aerogenes, Klebsiella oxytoca, Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter nosocomialis, Acinetobacter pittii, Acinetobacter haemolyticus, Acinetobacter johnsonii, Acinetobacter lwoffii, Acinetobacter radioresistens, Acinetobacter ursingii, Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas putida, Enterobacter cloacae, Enterobacter aerogenes, Stenotrophomonas maltophilia, Citrobacter freundii, Citrobacter koseri, Citrobacter sedlakii, Citrobacter braakii, Morganella morganii, Providencia rettgeri, Providencia stuartii, Salmonella typhimurium, Shigella dysenteriae, Moraxella catarrhalis, Neisseria gonorrhoeae, Propionibacterium acnes, Clostridioides difficile, Clostridioides perfringens, Bacteroides fragilis, Prevotella bivia, Eggerthella lenta, Peptostreptococcus anaerobius, and any combination thereof. In certain embodiments, the method further comprises administering at least one additional antibiotic. In certain embodiments, the additional antibiotic is at least one selected from the group consisting of a aminoglycoside, β-lactam (e.g., penicillin, cephalosporin, or carbapenem), monobactam, fluoroquinolone, sulfonamide, tetracycline, and macrolide. In certain embodiments, the additional antibiotic is at least one selected from the group consisting of amikacin, ampicillin, amoxicillin, aminoglycoside, azithromycin, aztreonam, carbapenem, cefepime, cefiderocol, cefotaxime, ceftriaxone, ceftaroline, ceftazidime, ceftobiprole, ceftolozane, ciprofloxacin, clindamycin, dalbavancin, daptomycin, doxycycline, ertapenem, fluoroquinolone, gentamicin, imipenem, levofloxacin, linezolid, meropenem, minocycline, mupirocin, oritavancin, piperacillin, streptogramin, sulbactam, tedizolid, telavancin, tigecycline, ticarcillin, tobramycin, trimethoprim/sulfamethoxazole, and vancomycin, or a combination thereof. In certain embodiments, the bacterial infection is a persistent or antibiotic resistant - 62 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) bacterial infection. In certain embodiments, formation of a bacterial biofilm is at least partially prevented or inhibited. In certain embodiments, the infection occurs on a prosthesis or an implant. In certain embodiments, the prosthesis selected from the group consisting of a knee prosthesis, a hip prosthesis, elbow prosthesis, ankle prosthesis, shoulder prosthesis, and spine prosthesis. In certain embodiments, the subject is a mammal. In certain embodiments, the mammal is a human. The methods described herein include administering to the subject a therapeutically effective amount of at least one compound described herein, which is optionally formulated in a pharmaceutical composition. In various embodiments, a therapeutically effective amount of at least one compound described herein present in a pharmaceutical composition is the only therapeutically active compound in a pharmaceutical composition. In certain embodiments, the method further comprises administering to the subject an additional therapeutic agent that treats a disease state. In certain embodiments, administering the compound(s) described herein to the subject allows for administering a lower dose of the additional therapeutic agent as compared to the dose of the additional therapeutic agent alone that is required to achieve similar results in treating a disease state in the subject. For example, in certain embodiments, the compound(s) described herein enhance(s) the activity of the additional therapeutic compound, thereby allowing for a lower dose of the additional therapeutic compound to provide the same effect. In certain embodiments, the compound(s) described herein and the therapeutic agent are co-administered to the subject. In other embodiments, the compound(s) described herein and the therapeutic agent are coformulated and co-administered to the subject. In certain embodiments, the subject is a mammal. In other embodiments, the mammal is a human Combination Administration and Treatment In various embodiments, a synergistic effect is observed when a compound as described herein is administered with one or more additional therapeutic agents or compounds. A synergistic effect may be calculated, for example, using suitable methods such as, for example, the Sigmoid-Emax equation (Holford & Scheiner, 1981, Clin. Pharmacokinet. 6:429-453), the equation of Loewe additivity (Loewe & Muischnek, 1926, Arch. Exp. Pathol - 63 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) Pharmacol.114:313-326) and the median-effect equation (Chou & Talalay, 1984, Adv. Enzyme Regul.22:27-55). Each equation referred to above may be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination. The corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively. Administration/Dosage/Formulations The regimen of administration may affect what constitutes an effective amount. The therapeutic formulations may be administered to the subject either prior to or after the onset of a disease state. Further, several divided dosages, as well as staggered dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection. Further, the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation. Administration of the compositions described herein to a patient, preferably a mammal, more preferably a human, may be carried out using known procedures, at dosages and for periods of time effective to treat a disease state in the patient. An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the state of the disease or disorder in the patient; the age, sex, and weight of the patient; and the ability of the therapeutic compound to treat a disease state in the patient. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A non-limiting example of an effective dose range for a therapeutic compound described herein is from about 1 and 5,000 mg/kg of body weight/per day. One of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation. Actual dosage levels of the active ingredients in the pharmaceutical compositions described herein may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. In particular, the selected dosage level depends upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or - 64 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts. A medical doctor, e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds described herein employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. In particular embodiments, it is especially advantageous to formulate the compound in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle. The dosage unit forms of the compound(s) described herein are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding/formulating such a therapeutic compound. In certain embodiments, the compositions described herein are formulated using one or more pharmaceutically acceptable excipients or carriers. In certain embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of a compound described herein and a pharmaceutically acceptable carrier. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable compositions may be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin. In certain embodiments, the compositions described herein are administered to the - 65 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) patient in dosages that range from one to five times per day or more. In other embodiments, the compositions described herein are administered to the patient in range of dosages that include, but are not limited to, once every day, every two, days, every three days to once a week, and once every two weeks. It is readily apparent to one skilled in the art that the frequency of administration of the various combination compositions described herein varies from individual to individual depending on many factors including, but not limited to, age, disease or disorder to be treated, gender, overall health, and other factors. Thus, administration of the compounds and compositions described herein should not be construed to be limited to any particular dosage regime and the precise dosage and composition to be administered to any patient is determined by the attending physician taking all other factors about the patient into account. The compound(s) described herein for administration may be in the range of from about 1 µg to about 10,000 mg, about 20 µg to about 9,500 mg, about 40 µg to about 9,000 mg, about 75 µg to about 8,500 mg, about 150 µg to about 7,500 mg, about 200 µg to about 7,000 mg, about 350 µg to about 6,000 mg, about 500 µg to about 5,000 mg, about 750 µg to about 4,000 mg, about 1 mg to about 3,000 mg, about 10 mg to about 2,500 mg, about 20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 30 mg to about 1,000 mg, about 40 mg to about 900 mg, about 50 mg to about 800 mg, about 60 mg to about 750 mg, about 70 mg to about 600 mg, about 80 mg to about 500 mg, and any and all whole or partial increments therebetween. In some embodiments, the dose of a compound described herein is from about 1 mg and about 2,500 mg. In some embodiments, a dose of a compound described herein used in compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Similarly, in some embodiments, a dose of a second compound as described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof. In various embodiments, the compound(s) described herein can be administered to a - 66 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) subject in an amount ranging from about 0.01 mg/kg to about 200 mg/kg, or about 0.5 mg/kg to about 190 mg/kg, or about 0.75 mg/kg to about 180 mg/kg, or about 1 mg/kg to about 170 mg/kg, or about 1.5 mg/kg to about 160 mg/kg, or about 2 mg/kg to about 150 mg/kg, or about 2.5 mg/kg to about 140 mg/kg, or about 3 mg/kg to about 130 mg/kg, or about 3.5 mg/kg to about 120 mg/kg, or about 4 mg/kg to about 110 mg/kg, or about 4.5 mg/kg to about 100 mg/kg, or about 5 mg/kg to about 95 mg/kg, or about 5.5 mg/kg to about 90 mg/kg, or about 6 mg/kg to about 85 mg/kg, or about 6.5 mg/kg to about 80 mg/kg, or about 7 mg/kg to about 75 mg/kg, or about 7.5 mg/kg to about 70 mg/kg, or about 8 mg/kg to about 65 mg/kg, or about 8.5 mg/kg to about 60 mg/kg, or about 9 mg/kg to about 55 mg/kg or about 9.5 mg/kg to about 50 mg/kg, or about 10 mg/kg to about 45 mg/kg. In various embodiments, the compound(s) described herein can be administered to a subject in an amount that is less than, equal to, or greater than about 0.01 mg/kg, 0.05 mg/kg, 0.1 mg/kg, 0.25 mg/kg, 0.5 mg/kg, 0.75 mg/kg, 1 mg/kg, 1.5 mg/kg, 2 mg/kg, 2.5 mg/kg, 3 mg/kg, 3.5 mg/kg, 4 mg/kg, 4.5 mg/kg, 5 mg/kg, 5.5 mg/kg, 6 mg/kg, 6.5 mg/kg, 7 mg/kg, 7.5 mg/kg, 8 mg/kg, 8.5 mg/kg, 9 mg/kg, 9.5 mg/kg, 10 mg/kg, 12 mg/kg, 14 mg/kg, 16 mg/kg, 18 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 55 mg/kg, 60 mg/kg, 65 mg/kg, 70 mg/kg, 75 mg/kg, 80 mg/kg, 85 mg/kg, 90 mg/kg, 100 mg/kg, 105 mg/kg, 110 mg/kg, 115 mg/kg, 120 mg/kg, 125 mg/kg, 130 mg/kg, 140 mg/kg, 145 mg/kg, 150 mg/kg, 155 mg/kg, 160 mg/kg, 170 mg/kg, 175 mg/kg, 180 mg/kg, 185 mg/kg, 190 mg/kg, 195 mg/kg, or 200 mg/kg. In certain embodiments, a composition as described herein is a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound described herein, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat, prevent, or reduce one or more symptoms of a disease state or disorder in a patient. Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art. The pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like. They may also be combined where desired with other active agents, e.g., other analgesic agents. Routes of administration of any of the compositions described herein include oral, - 67 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical. The compounds for use in the compositions described herein can be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration. Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions described herein are not limited to the particular formulations and compositions that are described herein. Oral Administration For oral application, particularly suitable are tablets, dragees, liquids, drops, suppositories, or capsules, caplets and gelcaps. The compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate. The tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent. For oral administration, the compound(s) described herein can be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., polyvinylpyrrolidone, hydroxypropylcellulose or hydroxypropyl methylcellulose); fillers (e.g., cornstarch, lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrates (e.g., sodium starch glycollate); or wetting agents (e.g., sodium lauryl sulphate). If desired, the tablets may be coated using suitable methods and coating materials such as OPADRY™ film - 68 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) coating systems available from Colorcon, West Point, Pa. (e.g., OPADRY™ OY Type, OYC Type, Organic Enteric OY-P Type, Aqueous Enteric OY-A Type, OY-PM Type and OPADRY™ White, 32K18400). Liquid preparation for oral administration may be in the form of solutions, syrups or suspensions. The liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxy benzoates or sorbic acid). Compositions as described herein can be prepared, packaged, or sold in a formulation suitable for oral or buccal administration. A tablet that includes a compound as described herein can, for example, be made by compressing or molding the active ingredient, optionally with one or more additional ingredients. Compressed tablets may be prepared by compressing, in a suitable device, the active ingredient in a free-flowing form such as a powder or granular preparation, optionally mixed with one or more of a binder, a lubricant, an excipient, a surface active agent, and a dispersing agent. Molded tablets may be made by molding, in a suitable device, a mixture of the active ingredient, a pharmaceutically acceptable carrier, and at least sufficient liquid to moisten the mixture. Pharmaceutically acceptable excipients used in the manufacture of tablets include, but are not limited to, inert diluents, granulating and disintegrating agents, dispersing agents, surface-active agents, disintegrating agents, binding agents, and lubricating agents. Suitable dispersing agents include, but are not limited to, potato starch, sodium starch glycollate, poloxamer 407, or poloxamer 188. One or more dispersing agents can each be individually present in the composition in an amount of about 0.01% w/w to about 90% w/w relative to weight of the dosage form. One or more dispersing agents can each be individually present in the composition in an amount of at least, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w/w relative to weight of the dosage form. Surface-active agents (surfactants) include cationic, anionic, or non-ionic surfactants, or combinations thereof. Suitable surfactants include, but are not limited to, behentrimonium chloride, benzalkonium chloride, benzethonium chloride, benzododecinium bromide, carbethopendecinium bromide, cetalkonium chloride, cetrimonium bromide, cetrimonium chloride, cetylpyridine chloride, didecyldimethylammonium chloride, dimethyldioctadecylammonium bromide, dimethyldioctadecylammonium chloride, domiphen - 69 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) bromide, lauryl methyl gluceth-10 hydroxypropyl dimonium chloride, tetramethylammonium hydroxide, thonzonium bromide, stearalkonium chloride, octenidine dihydrochloride, olaflur, N-oleyl-1,3-propanediamine, 2-acrylamido-2-methylpropane sulfonic acid, alkylbenzene sulfonates, ammonium lauryl sulfate, ammonium perfluorononanoate, docusate, disodium cocoamphodiacetate, magnesium laureth sulfate, perfluorobutanesulfonic acid, perfluorononanoic acid, perfluorooctanesulfonic acid, perfluorooctanoic acid, potassium lauryl sulfate, sodium alkyl sulfate, sodium dodecyl sulfate, sodium laurate, sodium laureth sulfate, sodium lauroyl sarcosinate, sodium myreth sulfate, sodium nonanoyloxybenzenesulfonate, sodium pareth sulfate, sodium stearate, sodium sulfosuccinate esters, cetomacrogol 1000, cetostearyl alcohol, cetyl alcohol, cocamide diethanolamine, cocamide monoethanolamine, decyl glucoside, decyl polyglucose, glycerol monostearate, octylphenoxypolyethoxyethanol CA-630, isoceteth-20, lauryl glucoside, octylphenoxypolyethoxyethanol P-40, Nonoxynol-9, Nonoxynols, nonyl phenoxypolyethoxylethanol (NP-40), octaethylene glycol monododecyl ether, N-octyl beta- D-thioglucopyranoside, octyl glucoside, oleyl alcohol, PEG-10 sunflower glycerides, pentaethylene glycol monododecyl ether, polidocanol, poloxamer, poloxamer 407, polyethoxylated tallow amine, polyglycerol polyricinoleate, polysorbate, polysorbate 20, polysorbate 80, sorbitan, sorbitan monolaurate, sorbitan monostearate, sorbitan tristearate, stearyl alcohol, surfactin, Triton X-100, and Tween 80. One or more surfactants can each be individually present in the composition in an amount of about 0.01% w/w to about 90% w/w relative to weight of the dosage form. One or more surfactants can each be individually present in the composition in an amount of at least, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w/w relative to weight of the dosage form. Suitable diluents include, but are not limited to, calcium carbonate, magnesium carbonate, magnesium oxide, sodium carbonate, lactose, microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate, and sodium phosphate, Cellactose ® 80 (75 % ^- lactose monohydrate and 25 % cellulose powder), mannitol, pre-gelatinized starch, starch, sucrose, sodium chloride, talc, anhydrous lactose, and granulated lactose. One or more diluents can each be individually present in the composition in an amount of about 0.01% w/w to about 90% w/w relative to weight of the dosage form. One or more diluents can each be individually present in the composition in an amount of at least, greater than, or less than - 70 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w/w relative to weight of the dosage form. Suitable granulating and disintegrating agents include, but are not limited to, sucrose, copovidone, corn starch, microcrystalline cellulose, methyl cellulose, sodium starch glycollate, pregelatinized starch, povidone, sodium carboxy methyl cellulose, sodium alginate, citric acid, croscarmellose sodium, cellulose, carboxymethylcellulose calcium, colloidal silicone dioxide, crosspovidone and alginic acid. One or more granulating or disintegrating agents can each be individually present in the composition in an amount of about 0.01% w/w to about 90% w/w relative to weight of the dosage form. One or more granulating or disintegrating agents can each be individually present in the composition in an amount of at least, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w/w relative to weight of the dosage form. Suitable binding agents include, but are not limited to, gelatin, acacia, pre-gelatinized maize starch, polyvinylpyrrolidone, anhydrous lactose, lactose monohydrate, hydroxypropyl methylcellulose, methylcellulose, povidone, polyacrylamides, sucrose, dextrose, maltose, gelatin, polyethylene glycol. One or more binding agents can each be individually present in the composition in an amount of about 0.01% w/w to about 90% w/w relative to weight of the dosage form. One or more binding agents can each be individually present in the composition in an amount of at least, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w/w relative to weight of the dosage form. Suitable lubricating agents include, but are not limited to, magnesium stearate, calcium stearate, hydrogenated castor oil, glyceryl monostearate, glyceryl behenate, mineral oil, polyethylene glycol, poloxamer 407, poloxamer 188, sodium laureth sulfate, sodium benzoate, stearic acid, sodium stearyl fumarate, silica, and talc. One or more lubricating agents can each be individually present in the composition in an amount of about 0.01% w/w to about 90% w/w relative to weight of the dosage form. One or more lubricating agents can each be individually present in the composition in an amount of at least, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w/w relative to weight of the dosage form. Tablets can be non-coated or they may be coated using known methods to achieve - 71 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) delayed disintegration in the gastrointestinal tract of a subject, thereby providing sustained release and absorption of the active ingredient. By way of example, a material such as glyceryl monostearate or glyceryl distearate may be used to coat tablets. Further by way of example, tablets may be coated using methods described in U.S. Patent Nos.4,256,108; 4,160,452; and 4,265,874 to form osmotically controlled release tablets. Tablets may further comprise a sweetening agent, a flavoring agent, a coloring agent, a preservative, or some combination of these in order to provide for pharmaceutically elegant and palatable preparation. Tablets can also be enterically coated such that the coating begins to dissolve at a certain pH, such as at about pH 5.0 to about pH 7.5, thereby releasing a compound as described herein. The coating can contain, for example, EUDRAGIT ® L, S, FS, and/or E polymers with acidic or alkaline groups to allow release of a compound as described herein in a particular location, including in any desired section(s) of the intestine. The coating can also contain, for example, EUDRAGIT ® RL and/or RS polymers with cationic or neutral groups to allow for time controlled release of a compound as described herein by pH-independent swelling. Parenteral Administration For parenteral administration, the compounds as described herein may be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose and/or continuous infusion. Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing and/or dispersing agents may be used. Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution and isotonic sodium chloride solution. Sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain - 72 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) alcohol diluent or dispersant, such as such as lauryl, stearyl, or oleyl alcohols, or similar alcohol. Additional Administration Forms Additional dosage forms suitable for use with the compound(s) and compositions described herein include dosage forms as described in U.S. Patents Nos.6,340,475; 6,488,962; 6,451,808; 5,972,389; 5,582,837; and 5,007,790. Additional dosage forms suitable for use with the compound(s) and compositions described herein also include dosage forms as described in U.S. Patent Applications Nos.20030147952; 20030104062; 20030104053; 20030044466; 20030039688; and 20020051820. Additional dosage forms suitable for use with the compound(s) and compositions described herein also include dosage forms as described in PCT Applications Nos. WO 03/35041; WO 03/35040; WO 03/35029; WO 03/35177; WO 03/35039; WO 02/96404; WO 02/32416; WO 01/97783; WO 01/56544; WO 01/32217; WO 98/55107; WO 98/11879; WO 97/47285; WO 93/18755; and WO 90/11757. Controlled Release Formulations and Drug Delivery Systems In certain embodiments, the formulations described herein can be, but are not limited to, short-term, rapid-offset, as well as controlled, for example, sustained release, delayed release and pulsatile release formulations. The term sustained release is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that may, although not necessarily, result in substantially constant blood levels of a drug over an extended time period. The period of time may be as long as a month or more and should be a release which is longer that the same amount of agent administered in bolus form. For sustained release, the compounds may be formulated with a suitable polymer or hydrophobic material which provides sustained release properties to the compounds. As such, the compounds for use with the method(s) described herein may be administered in the form of microparticles, for example, by injection or in the form of wafers or discs by implantation. In some cases, the dosage forms to be used can be provided as slow or controlled- release of one or more active ingredients therein using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, or microspheres or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the pharmaceutical compositions described herein. Thus, single unit dosage - 73 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) forms suitable for oral administration, such as tablets, capsules, gelcaps, and caplets, that are adapted for controlled-release are encompassed by the compositions and dosage forms described herein. Most controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance. In addition, controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood level of the drug, and thus can affect the occurrence of side effects. Most controlled-release formulations are designed to initially release an amount of drug that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled-release of an active ingredient can be stimulated by various inducers, for example pH, temperature, enzymes, water, or other physiological conditions or compounds. The term “controlled-release component” is defined herein as a compound or compounds, including, but not limited to, polymers, polymer matrices, gels, permeable membranes, liposomes, or microspheres or a combination thereof that facilitates the controlled-release of the active ingredient. In some embodiments, the compound(s) described herein are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation. In some embodiments, the compound(s) described herein are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation. The term delayed release is used herein in its conventional sense to refer to a drug formulation that provides for an initial release of the drug after some delay following drug administration and that mat, although not necessarily, includes a delay of from about 10 minutes up to about 12 hours. The term pulsatile release is used herein in its conventional sense to refer to a drug formulation that provides release of the drug in such a way as to produce pulsed plasma - 74 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) profiles of the drug after drug administration. The term immediate release is used in its conventional sense to refer to a drug formulation that provides for release of the drug immediately after drug administration. As used herein, short-term refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes and any or all whole or partial increments thereof after drug administration after drug administration. As used herein, rapid-offset refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any and all whole or partial increments thereof after drug administration. Dosing The therapeutically effective amount or dose of a compound described herein depends on the age, sex and weight of the patient, the current medical condition of the patient and the progression of a disease state in the patient being treated. The skilled artisan is able to determine appropriate dosages depending on these and other factors. A suitable dose of a compound described herein can be in the range of from about 0.01 mg to about 5,000 mg per day, such as from about 0.1 mg to about 1,000 mg, for example, from about 1 mg to about 500 mg, such as about 5 mg to about 250 mg per day. The dose may be administered in a single dosage or in multiple dosages, for example from 1 to 4 or more times per day. When multiple dosages are used, the amount of each dosage may be the same or different. For example, a dose of 1 mg per day may be administered as two 0.5 mg doses, with about a 12-hour interval between doses. It is understood that the amount of compound dosed per day may be administered, in non-limiting examples, every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days. For example, with every other day administration, a 5 mg per day dose may be initiated on Monday with a first subsequent 5 mg per day dose administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday, and so on. In the case wherein the patient’s status does improve, upon the doctor’s discretion the administration of the compound(s) described herein is optionally given continuously; alternatively, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”). The length of the drug holiday optionally varies between 2 days and 1 year, including by way of example only, 2 days, 3 - 75 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dose reduction during a drug holiday includes from 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. Once improvement of the patient’s conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, is reduced to a level at which the improved disease is retained. In certain embodiments, patients require intermittent treatment on a long-term basis upon any recurrence of symptoms and/or infection. The compounds described herein can be formulated in unit dosage form. The term “unit dosage form” refers to physically discrete units suitable as unitary dosage for patients undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose. Toxicity and therapeutic efficacy of such therapeutic regimens are optionally determined in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LD50 and ED50. The data obtained from cell culture assays and animal studies are optionally used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized. EXAMPLES Various embodiments of the present application can be better understood by reference to the following Examples which are offered by way of illustration. The scope of the present application is not limited to the Examples given herein. Materials and Methods - 76 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) Screening of small molecules that bind MCR-1 A DNA-encoded libraries encompassing 6 billion compounds using technology developed as described in Clark, Matthew A., et al. "Design, synthesis and selection of DNA- encoded small-molecule libraries." Nature chemical biology 5.9 (2009): 647-654. These libraries are made by a split-and-pool method whereby three cycles of synthesis are performed with various building blocks at each step. A double-stranded DNA barcode unique to each building block is ligated at each cycle to encode the synthesis. Purified, His-tagged, MCR-1 protein was used to screen DECL libraries. The libraries were incubated with MCR-1 and the complexes were captured using Nickel-beads and washed. Bound small molecules were released and bound again to fresh MCR-1 protein for two additional rounds of enrichment. After the final elution, the DNA section of the conjugates was amplified by PCR and subjected to deep sequencing. Bioinformatics analysis was used to reveal the sequences most highly represented after the binding selection as described in Faver, John C., et al. "Quantitative comparison of enrichment from DNA-encoded chemical library selections." ACS combinatorial science 21.2 (2019): 75-82. Because the barcode DNA sequence encodes the small molecule building blocks added, it reveals the structure of library members that bound the target protein. DNA sequencing revealed several compounds were enriched after affinity selection with MCR-1. Based on these results, three compounds were chosen for re- synthesis in the absence of the DNA-tag for further testing (FIG.6). Testing CDD compounds against MCR-containing clinical strains A spot assay to assess the activity of several CDD compounds versus colistin-resistant clinical strains containing MCR-1. The clinical isolates were obtained from the CDC & FDA Antibiotic Resistance Isolate Bank. These strains are validated to contain MCR-1 and are colistin resistant. One strain of Klebsiella pneumoniae and three strains of E. coli were tested (FIG.11). Spot assays were performed with 0.8 μg/ml colistin and 12.5 μM compound. Six compounds were evaluated including CDD-2901, CDD-2750, CDD-3002, CDD-2918, CDD- 2902, CDD-3019, and CDD-2847 (FIGs.9-10). All of these compounds showed significant activity by the spot assay (>100x) and, for some, MIC against E. coli XL1-Blue encoding MCR- 1 (FIGs.9-10). Docking CDD-1794 and CDD-1938 to an MCR-1 homology model- The structure of full-length MCR-1 is not known. In lieu of a structure, a homology model was constructed based on the structure of NmEptA, which has 37% sequence identity - 77 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) to MCR-1. Autodock Vina was used to computationally dock CDD-1794 and CDD-1938 to the MCR-1 homology model (FIGs.8A-8B). The highest ranked pose of each compound is bound in a similar pocket near the catalytic Thr285 residue. The compounds are predicted to bind in a similar position as where dodecyl-β-D-maltoside was found in the NmEptA structure and was proposed as the phosphatidylethanolamine binding site. Testing CDD compounds for cytotoxicity versus human cells An important question is whether the compounds that have activity against strains expressing MCR-1 are cytotoxic to human cells. This was addressed in cytotoxicity testing using human HepG2 cells. A set of potent compounds including CDD-2750, CDD-2901, CDD-2847, and CDD-2902 was tested. A HepG2 cell line was used to screen for in vitro metabolism-associated drug toxicity using cell viability assays that measure the number of live cells after a 24-hour incubation with increasing concentrations (0-100 µM) of compounds. A CellTiter-Glo^ Luminescent Cell Viability Assay was used to determine the number of viable cells in culture. Bacterial strains and expression vectors E. coli XL1-Blue (Stratagene) and E. coli BL21(DE3) were used as the host strains for overproduction of wild-type or mutant MCR-1 enzyme, respectively. For the construction of the MCR-1 recombinant plasmid, a Strep-tag II-fused MCR-1 (MCR-1-StrepII) was amplified from pBCKSII-MCR-1 using Pfu polymerase (Invitrogen) and cloned between SacI and XbaI restriction sites of the chloramphenicol-resistant pTP470 plasmid to obtain MCR-1-StrepII-pTP470, on which the expression of MCR-1 was under the control of an isopropyl-β-d-thiogalactopyranoside (IPTG)-inducible trc promoter. Although, originally, the inclusion of Strep-tag II at the C-terminus of MCR-1 was used to monitor the expression of MCR-1 in E. coli by immunoblotting with anti-Strep tag II antibody, it was not used in this study. The Strep tag II-modified MCR-1 plasmid construct was shown to provide colistin resistance to E. coli XL1-Blue cells. For overexpression and purification of MCR-1, mcr-1 was cloned between NdeI and XhoI restriction sites of a modified pET28a vector (Novogen), in which the thrombin recognition sequence was replaced with the tobacco etch virus (TEV) protease recognition sequence and 2 extra codons for histidine residues were inserted before the TEV protease recognition sequence to increase binding affinity of His-tagged target proteins to the HisTrap - 78 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) columns. The clinical isolates (independently determined to have plasmid-encoded antibiotic resistance genes and microdilution MICs based on CLSI testing standards where the resistance cut-off is 4 ^g/mL) were obtained from the Center for Disease Control & Prevention (CDC)/US Food & Drug Administration (FDA) Antibiotic Resistance (AR) Isolate Bank panel entitled “Isolates with new or novel antibiotic resistance (NEW)”. The strains in the panel are as follows: K. pneumoniae AR Bank# 0497 (aac(6')-Ib-cr, aadA2, CTX-M-15, dfrA12, fosA, mcr-1, mph(A), oqxA, OXA-1, SHV-28, sul1, TEM-1B, tet(A); colistin MIC = 8 ^g/mL); E. coli AR Bank# 0495 (aadA5, dfrA17, mcr-1, mph(A), strB, sul2, TEM-1B, tet(A); colistin MIC = 4 ^g/mL); [E. coli clinical strain 0349 (aph(4)-Ia, CTX-M- 14, CTX-M-55, dfrA14, fosA, mcr-1, mph(A), strA, strB, TEM-1B, tet(A); colistin MIC = 2-4 ^g/mL)]; E. coli AR Bank# 0346 (aadA5, catA1, CMY-2, CTX-M-55, dfrA17, fosA, mcr-1, mph(A), rmtB, strA, strB, sul1, sul2; colistin MIC = 4 ^g/mL); E. coli AR Bank# 0538 (mcr- 2; colistin MIC = 8 ^g/mL); E. coli AR Bank# 0350 (mcr-1; colistin MIC = 4 ^g/mL); E. coli AR Bank# 0493 (mcr-1; colistin MIC = 8 ^g/mL); E. coli AR Bank# 0494 (mcr-1; colistin MIC = 8 ^g/mL). Overexpression and purification of wild-type MCR-1 enzyme The MCR-1-pET28a-TEV plasmid was used for overexpression of 8×His-tagged- MCR-1 (His-MCR-1) enzyme in E. coli BL21(DE3) cells. The E. coli cells containing the MCR-1 expression plasmid were grown at 37°C to an OD600 of 0.8 in LB medium containing 25 μg/ml kanamycin. Expression of the His-MCR-1 protein was induced with 0.5 mM IPTG at 18°C for 16 h. The cells were pelleted and suspended in lysis buffer (20 mM HEPES, 150 mM NaCl, pH 7.4) and lysed using a French press and a short period of sonication. The cell debris was removed by centrifugation at 12,000×g for 30 min, and the membranes were isolated by ultracentrifugation at 170,000xg for 1.5 hours at 4°C. His-MCR-1 was solubilized from the membranes by incubating the isolated membranes at 4°C overnight with gentle shaking with 20 mM n-dodecyl-β-d-maltopyranoside (DDM) in 20 mM HEPES, pH 7.4, 300 mM NaCl, 1× EDTA-free protease inhibitor cocktail (Gendepot). The solubilized His- MCR-1 was separated from the membrane debris by ultracentrifugation at 170,000 × g for 1 hour at 4°C. Solubilized His-MCR-1 was purified by metal-chelating chromatography by loading the supernatant from the ultracentrifugation onto a 1-mL HisTrap FF column (GE - 79 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) Healthcare), which had been equilibrated by Buffer A (20 mM HEPES, pH 7.4, 300 mM NaCl, 20 mM imidazole, 0.5 mM DDM, 1 mM phenylmethylsulfonyl fluoride [PMSF]). After washing with 5 column volumes (CVs) of Buffer A, the bound proteins were eluted with 0 to 100% Buffer B (20 mM HEPES, pH 7.4, 300 mM NaCl, 500 mM imidazole, 0.5 mM DDM, 1 mM PMSF) over 10 CVs. Fractions containing His-MCR-1 were pooled, concentrated, and buffer exchanged to Buffer A with a 50-kDa cut-off Amicon Ultra-15 centrifugal filter unit (EMD Millipore). The His-tag was cleaved by incubating with TEV protease for 16 hours at 4°C at a ratio of 1:50, and the TEV protease was removed by incubating with Ni-Sepharose 6 fast-flow resin (GE Healthcare). MCR-1 was further purified by gel filtration chromatography using a Superdex 200 Increase GL 10/300 sizing column (GE Healthcare) with 20 mM HEPES, pH 7.4, 150 mM NaCl, 0.5 mM DDM, 1 mM PMSF as running buffer. Fractions containing MCR-1 were pooled and concentrated. The final protein concentration of MCR-1 was determined by measuring absorbance at 280 nm with a DU800 spectrophotometer (Beckman Coulter) and using an extinction coefficient of ε280 = 66,240 M−1 cm−1, which was calculated using the ExPASy ProtParam tool. SDS-PAGE analysis revealed that the purity of wild-type MCR-1 was higher than 95%. Affinity selection of DNA-Encoded Chemical Libraries The DNA-encoded chemical library (DECL) was mixed with 1 or 5 μM of His-MCR- 1 in 200 μL of selection buffer ([20 mM HEPES pH 7.5, 134 mM potassium acetate, 10 mM imidazole, 1 mM TCEP, 8 mM sodium acetate, 0.8 mM magnesium acetate, 1 mM CHAPS, 4 mM sodium chloride, and 0.1 mg/mL Sheared Salmon Sperm DNA]). The same library pool without protein was incubated under the same conditions as a non-target control (NTC) to assess the background binding of DECL molecules to the affinity resin. Before incubation, 1 μL of library molecules was set aside for quantitation using quantitative PCR (qPCR). Ni- NTA magnetic beads (50 μL) were pre-washed with selection buffer, and the target protein−library mixture was added for affinity selection. The magnetic beads were washed with 500 μL of selection buffer to remove unbound DECL molecules. Bound compounds were eluted by incubating the beads with 100 μL of selection buffer at 80 °C for 10 min. One μL of elution material was set aside for quantitation by qPCR, and the remaining volume was subjected to an additional round of affinity selection with fresh protein as described above. After 3 rounds of selection, qPCR was performed on recovered DECL material after each round of selection to monitor the total amount of DNA tags remaining. This information was used to guide both the selection process and sequencing preparation. An appropriate number - 80 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) of PCR cycles was used to amplify the DNA and added DNA sequences compatible with Illumina sequencing flow cells. The PCR product was purified using Agencourt AMPure XP SPRI beads (Agencourt, Danvers, MA) according to the manufacturer’s instructions and then quantitated on an Agilent BioAnalyzer (Santa Clara, CA) using a high-sensitivity DNA kit. The final concentration of amplicon for each sample was pooled at a 4 nM concentration. The final concentration of 1.8 pM of library pool samples was loaded onto an Illumina Next-Seq 500 sequencer (San Diego, CA). Selection output data were processed in-house. Spot assays Hit validation was accomplished using a microbiological technique called spot assay plating. Briefly, sterile Luria Bertani (LB) (Becton Dickinson) agar plates supplemented with 12.5 ^g/mL chloramphenicol (for plasmid maintenance) were prepared containing: 1) subinhibitory concentration (0.32 ^g/mL) of colistin sodium methane sulfonate (CMS) antibiotic only (adjusted for colistin base using an adjustment factor of 2.56X in water); 2) high inhibitor compound concentration (12.5 ^M) only and 3) no antibiotic/inhibitor, and test plates containing: 4) low inhibitor concentration (3.25 ^M) and CMS antibiotic (0.32 ^g/mL); 5) medium inhibitor concentration (6.25 ^M) and CMS antibiotic (0.32 ^g/mL), and 6) high inhibitor concentration (12.5 ^M) and CMS antibiotic (0.32 ^g/mL). Inhibitor stocks were dissolved in DMSO. Plates were used the following day with storage at 4ºC to allow complete hydrolysis of CMS to colistin. Plates were dried at 37ºC an hour before spotting to ensure the spots were absorbed onto the surface of the agar and to prevent spots from running into each other. Cultures from single colony forming units of E. coli/MCR-1 and E. coli/T285A MCR-1 were grown overnight in LB broth containing 12.5 ^g/mL chloramphenicol at 37ºC; the following day, the cultures were normalized to an OD600 = 1 and 10X dilutions were prepared in Eppendorf tubes using fresh LB/chloramphenicol media. Dilutions were transferred to a 96 well plate and a multichannel pipette was used to transfer 7 ^L of dilutions, prepared as biological triplicates, onto each of the control and test plates. Spots were allowed to dry by absorption, and plates were inverted and incubated at 37ºC overnight. Plates, without the lid, were photographed and growth was visually confirmed. Viability was our endpoint. Growth on the test plates was compared to growth on the control plates. Growth was defined as the presence of single colonies or overall growth coverage within the spot. Clinical isolates were sub-cultured from -80ºC freezer stocks onto 5% sheep blood agar plates and spot assays were prepared the same as the laboratory strains. - 81 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) Antimicrobial susceptibility testing Minimum inhibitory concentration (MIC) assays were performed in a 96-well format with a final volume of 100 ^L. Cultures from single colony forming units (CFUs) of E. coli XL1Blue/MCR-1 and E. coli XL1Blue/T285A MCR-1 were grown in LB or CAMH containing chloramphenicol (12.5 ^g/mL) overnight at 37ºC. Clinical isolates were sub- cultured from -80ºC freezer stocks onto 5% sheep blood agar plates and prepared in the same way as the laboratory strains following BSL2 guidelines. Two-fold dilutions of colistin sulfate (adjusted for colistin base using 1.46X adjustment factor) (Sigma Aldrich) were prepared fresh, in duplicate, in LB or cation-adjusted Mueller Hinton (CAMH) (Becton Dickinson) broth for final concentrations of 0, 0.01325, 0.0625, 0.125, 0.25, 0.5, 1, 2, 4, 8, 16 and 32 ^g/mL. These media/colistin dilutions were dispensed (93.75 ^L) into their respective 96-well flat bottom polystyrene plate wells using a multichannel pipette. Inhibitors were prepared fresh for final concentrations: 0 ^M, 6.25 ^M, 12.5 ^M, 25 ^M from 100 or 50 mM DMSO stocks; 1.25^L of inhibitor dilutions were dispensed into the respective wells filled with the media/colistin dilutions using a multichannel pipettor. Final DMSO concentration was 1.25%. Overnight cultures were normalized to an OD600 = 1 and further diluted to 104 CFUs/mL and 5 ^L were used to inoculate each well of the plate containing the 2-fold dilutions of colistin sulfate with or without inhibitor. MIC plates were incubated at 35ºC for 18-24 hours and read visually. The colistin MIC was defined as the lowest concentration of colistin ± inhibitor that inhibited visible growth of bacterial culture after overnight incubation. No inoculum controls were included. Time-kill curve assays Initially, growth curves were carried out to confirm that strains would reach a stable early to mid-log phase by 4-5 hours and inoculum was adjusted accordingly. Time-kill curve (TKC) assays were performed in a 96-well format with a final volume of 100 ^L per well. Briefly, E. coli XL1 Blue expressing MCR-1 or T285A MCR-1 were cultured in CAMH or LB broth with 12.5 ^g/mL chloramphenicol (Cm) from fresh single CFUs on CAMH-Cm or LB agar at 37ºC. Overnight cultures were normalized to an OD600 = 1 and further diluted to 104 CFUs/mL and for each strain, 90 ^L was added to each well of the plate. The plates were pre-incubated for 45 min with orbital shaking 300 rpm at 37^C. For the 96-well flat bottom polystyrene plate, the following treatments were prepared and examined: no antibiotic - 82 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) control, 4 ^g/mL colistin sulfate (Sigma Aldrich) only control (adjusted for colistin base using 1.46X adjustment factor) in duplicate, 12.5 ^M inhibitor (CDD-3003 or CDD-3356), 4 ^g/mL colistin with 1.56 ^M, 3.125 ^M, 6.25 ^M or 12.5 ^M inhibitor in duplicate. To each well containing 90 ^L of pre-incubated culture, 10 ^L of each treatment was added using a multichannel pipette, resulting in eight identical rows containing culture exposed to each of the treatments. The rows were assigned 0, 1, 2, 3, 4, 5, 6 and 24 hours. At each time point after exposure, 10 ^L of one entire row was transferred into a row of sterile 90 ^L PBS and diluted in six subsequent 10-fold dilution series; after thoroughly mixing with the pipette in between each dilution, 10 ^L of each diluted row was plated, in triplicate or more, onto the surface of pre-warmed CAMH-Cm plates. An additional 10 ^L of undiluted sample was also spotted. After spots dried, the plates were incubated overnight at 37^C. Then, CFUs were counted, and CFUs/mL were calculated for each well by multiplying total number of CFUs counted by the dilution factor and dividing by the spotted volume, 0.01 mL (10 ^L). Experiments were performed as two or more independent experiments. No inoculum controls were included. Synthesis of DNA-free compounds and their derivatives All chemical reagents were purchased from commercial sources and used without further purification. Solvents were purchased as either anhydrous grade products in sealed containers or reagent grade and used as received. Flash column chromatography was performed using an automated chromatography instrument with an appropriately sized silica column. Thin-layer chromatography was performed on silica gel 60 F254 plates (E. Merck). Non-UV active compounds were visualized on thin-layer chromatography (TLC) using one of the following stains: KMnO4, ninhydrin, p-anisaldehyde, 2,4-DNP, or bromocresol green. Liquid chromatography-mass spectrometry (LC-MS) used for data collection was a 1290 Infinity Series liquid chromatography with a 6150 mass spectrometer system (Agilent). The solid phase column was an Agilent Eclipse Plus C18, 2.1 mm × 50 mm (8 μm), and the mobile phase solvents were A: 0.05% formic acid in water and B: 5% water in acetonitrile. Peak detection was done at 254 and 230 nm. The high-resolution mass spectrometry (HRMS) data were acquired on a Thermo Q Exactive Orbitrap MS coupled with a Thermo Vanish UHPLC. The Zorbax XDB-C18 (4.6 mm × 50 mm, 3 μm) was used for separation and kept at 40 °C. The flow rate used was 0.3 mL/min with a gradient ranging from 2 to 95% aqueous acetonitrile containing 0.1% formic acid in a 7 min run. Q Exactive MS was operated in - 83 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) positive mode with electrospray ionization. The lock mass at m/z 371.1012 for positive mode was used as a reference ion during acquisition. All compounds are >95% pure by HPLC. NMR spectra were collected using a Bruker 600 or 151 MHz NMR for 1H and 13C, respectively. All NMR chemical shifts were referenced to the residual nondeuterated solvent as an internal standard. Signal multiplicities are described using the following abbreviations: s = singlet, d = doublet, t = triplet, b = broad, quar = quartet, quin = quintet, m = multiplet, v = very; abbreviations are combined, e.g., vbs = very broad singlet. Cell viability in HepG2 and primary human hepatocytes The HepG2 cell line and primary human hepatocytes (pHH) cells to were used to screen for in vitro metabolism-associated drug toxicity using cell viability assays that measure the number of live cells after a 24-hour incubation with increasing concentrations (0- 100uM) of compounds. We used the CellTiter-Glo^ Luminescent Cell Viability Assay to determine the number of viable cells in culture, where the amount of ATP in cells correlates with cell viability. The procedure involves adding the CellTiter-Glo^ reagent to the cells whereby it lyses the cell membranes to release ATP, the reagent inhibits endogenous ATPases and provides luciferin and luciferase needed to measure ATP using a bioluminescent reaction. A CLARIOstar plate reader was used to detect the signal and measure the ATP in viable cells. Alternately, when compound solubility was an issue, we used the CellTiter-Blue^ Cell Viability Assay, which uses an optimized reagent containing resazurin that can enter living cells where it is reduced to the fluorescent resorufin product; this conversion is proportional to the number of metabolically active, viable cells present in a culture. The HepG2 cells in the assay plate are incubated at 37°C for 24 hours. The signal is measured using a standard multi-well fluorometer. For both assays, normalized % viability is plotted as a function of compound concentration (uM), and non-linear regression (Log(concentration)-normalized cell viability) is used to calculate the half-maximal inhibitory concentration (IC50) with Prism 10.0. For IC50 cut-off values, compounds retaining 100X antimicrobial activity at a concentration equal to 10% of the IC50 were considered to have a low cytotoxicity profile. Example 1: DNA encoded library (DECL) screening for MCR-1 inhibitors An innovative aspect of the present disclosure is the use of DNA-encoded chemical library technology (DECL) to explore chemical space to identify small molecule high affinity - 84 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) binders for the clinically important MCR-1 mobile colistin resistance enzyme for discovery of novel inhibitors. The DECL approach involves the creation of libraries of drug-like molecules covalently attached to a unique DNA barcode that enables identification of binders for a target in a pool of millions of compounds (FIG.3). The conjugates are constructed in sequential cycles of chemical attachment of drug-like fragments (chemical building blocks) to a molecular scaffold concomitantly encoded through the ligation of a unique DNA barcode. The libraries can be screened against a tagged version of the protein target to identity molecules with high affinity, which are isolated though the pull-down of the tag from solution. Next-generation DNA sequencing allows the determination of the DNA barcode sequences isolated and, thus, the structures of the high-affinity compounds. The DECL approach was applied to identify small molecule inhibitors of the OXA-48 carbapenemase, NDM-1 metallo-β-lactamase, and SARS CoV-2 Mpro protease. The present example applies a similar strategy to identify inhibitors of MCR-1. An X-ray crystal structure of the soluble, periplasmic catalytic domain of the MCR-1 enzyme was solved and the protein was generated with a high level expression. Purification of active, full-length MCR-1 enzyme was also achieved to facilitate small molecule inhibitor discovery efforts. The goal was to identify potent inhibitors of MCR-1 that restore the effectiveness of current and future polymyxin antibiotics. Example 2: Crystal structure of the catalytic domain of MCR-1 The MCR-1 protein is predicted to consist of a membrane-spanning domain and a periplasmic catalytic domain. The X-ray crystal of the catalytic domain (cMCR) was determined at 1.32 Å resolution. cMCR-1 is a zinc metallo-enzyme that assumes a α/β/α fold characteristic of the alkaline phosphatase superfamily. Based on the structure and knowledge of the alkaline phosphatase mechanism, an active-site zinc in an analogous position as the catalytic zinc in alkaline phosphatase may stabilize the alkoxide form of Thr285 for nucleophilic attack on the phosphate of the phosphatidylethanolamine substrate to create an intermediate with Thr285 linked to PEA. Binding of lipid A in an appropriate position for nucleophilic attack on the lipid A 1’ or 4’ phosphate on the phosphate of the Thr285-PEA intermediate could then transfer the group to lipid A. Molecular dynamics simulations, density functional theory, and ab initio calculations suggest a mechanism consistent with this model. Example 3: MCR-1 expression reduces E. coli susceptibility to polymyxins - 85 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) If Thr285 is the catalytic nucleophile, mutation of this residue would be expected to greatly decrease MCR-1 function. This was tested by mutating this residue to alanine in a plasmid encoding the full-length mcr-1 gene and measuring the minimum inhibitory concentration (MIC) of colistin and polymyxin B. The strain containing wild-type mcr-1 exhibited MICs of 8.0 and 6.0 μg/ml for colistin and polymyxin B, respectively, compared to an MIC of 0.032 μg/ml for the control strain containing the plasmid without mcr-1 (Table 2). Therefore, the full-length MCR-1 is functional and provides resistance in E. coli. Mutation of Thr285 to alanine lowers the colistin and polymyxin B MICs to near the control levels (Table 2). This result indicates the full-sized MCR-1 is active and that Thr285 is important for MCR-1 function, consistent with it serving as the catalytic nucleophile. This further establishes the role that the plasmid gene expression has on resisting antibiotics including colistin and polymyxin B. Table 2. MICs (µg/mL) for E. coli BL21(DE3) containing a plasmid encoding wild-type MCR-1 and MCR-1 T285A. WT MCR-1 E. coli MIC T285A MCR-1 E. coli MIC Plasmid description (µg/mL) (µg/mL) pET28a (empty vector) 0.032 0.032 mcr-1 pET28a 8.0 6.0 mcr-1 T285A pET28a 0.125 0.092 Example 4: Expression and purification of catalytically active MCR-1 The first step towards using the DECL approach to identity inhibitors is the successful expression and purification of the full-sized MCR-1 containing the catalytic and membrane domains. For this purpose, the full-length mcr-1 gene was cloned into the pET28a E. coli protein expression plasmid with an N-terminal His-tag. This plasmid provides E. coli with resistance to colistin indicating the full-length, His-tagged enzyme is active. The expressed protein was localized to the membrane fraction by Western blot. Based on these findings, the protein was expressed in E. coli and a cell lysate was solubilized using 30 mM dodecyl-β-D- maltoside (DDM) detergent, centrifuged, and the supernatant was filtered and subjected to affinity purification using a nickel-sepharose resin. The His-tag was removed by with TEV protease and separated from MCR-1 on a nickel-charged resin. The MCR-1 protein was then further purified by size exclusion chromatography. The final preparation contains - 86 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) approximately 95% pure MCR-1 protein (FIG.4). The activity of the purified MCR-1 was tested using a biochemical assay in which fluorescently labeled phosphatidylethanolamine is incubated with the enzyme. The products of the reaction were subsequently assayed by thin layer chromatography (TLC) to show phosphoethanolamine is removed from the lipid by the enzyme. This assay was performed using full-sized MCR-1 and the MCR-1 T285A enzyme lacking the key catalytic residue as a control. The reaction products were visualized by TLC. As seen in FIG.5A, MCR-1 removes phosphoethanolamine from the fluorescent substrate but the MCR-1 T285A enzyme does not, showing the purified enzyme is active and the reaction is dependent on the MCR-1 active site. Example 5: MIC determination of certain exemplary antibacterial compounds The initial structure activity relationship was focused on CDD-1938 due to its higher potency relative to CDD-1794 (Table 2). Due to the low throughput and expense of monitoring the NBD-PEA to NBD-DG conversion by TLC (FIG.5B), compounds were assayed directly against E. coli encoding MCR-1 using the spot test on agar plates containing colistin and the compound of interest (FIGs.7A-7F). As seen for the parent compound, CDD- 1938, E. coli containing MCR-1 growing on agar plates containing 0.8 μg/mL colistin and 12.5 μg/ml CDD-1938 grows to a 10-fold lower dilution (FIG.7F) versus plates containing 0.8 μg/ml colistin with no inhibitor (FIG.7C). Therefore, this is scored as a 10X effect of CDD-1938. Note that the effect on growth for E. coli containing MCR-1 T285A on agar plates containing 0.8 μg/ml colistin and 12.5 μg/ml CDD-1938 versus colistin alone suggesting the compound is acting on MCR-1 enzyme activity. The predicted binding mode of the DECL hit for CDD-1938 is shown in FIG.9. The DNA is attached via a linker to the C1 position while the C2 position branches from C1 and C3 branches from the C2 position. The CDD-1938 compound that was synthesized off-DNA and shows activity against E. coli expressing MCR-1 contains C1, C2, and C3 substituents. CDD-1938 is a racemic mixture with a chiral center at the phenyl substitution on the piperazine ring on C1. Both enantiomers of CDD-2778 (R-enantiomer) grew up to a 100-fold lower dilution than the colistin only control, which reflects a 10-fold increase in potency compared to CDD-1938, while E. coli/MCR-1 on plates with colistin and 12.5 μg/ml CDD- 2748 (S-enantiomer) grew up to a 10-fold lower dilution versus the colistin only control, indicating the R-enantiomer is more potent and was therefore the focus of subsequent work. The benzylamide-containing moiety that served as a linker to the DNA was tested for its - 87 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) relevance or contribution to potency by removing the group to create CDD-2750. E. coli/MCR-1 grew to a 1000-fold lower dilution on plates with colistin and 12.5 μg/ml compound compared to the colistin only control. Thus, removal of the benzylamide moiety results in a further 10-fold increase in potency compared to CDD-2778 and a 100-fold increase compared to CDD-1938. The next assessment was the importance of the nitrogen in the pyridine ring in the C2 position. The pyridine ring in CDD-2750 was changed to a benzyl ring to create CDD-2901 and the spot assay showed no change in potency, indicating the nitrogen was not critical for inhibition. The importance of the isopropyl phenyl in the C3 position was tested by synthesizing CDD-2932, which lacks the C3 group. CDD-2932 shows a 100-fold loss in potency in the spot assay compared to the CDD-2750 parent compound, indicating the C3 group makes important contributions to binding. CDD-2889, which retains the C3 phenyl but is lacking the isopropyl group also showed a 100-fold decrease in potency relative to the CDD-2750 parent, revealing the importance of the isopropyl group for inhibition. The original CDD-1938 hit compound and the more potent CDD-2750 analog contain a halide (Cl) appended to the phenyl group at the C1 position. CDD-2835 is CDD-2750 lacking the halide. This compound showed a 100-fold loss in potency relative to CDD-2750, indicating the importance of the halide for potency. The Cl in CDD-2750 was replaced with fluorine (F) to create CDD-3228, which displayed similar potency in the spot assay as CDD- 2750. The Cl was also replaced by F in CDD-2901, which has a benzyl rather than a pyridine ring at C2, to create CDD-3002. CDD-3002 showed similar potency as CDD-2901 in the spot assay. Thus, both of the F-containing compounds exhibited similar potency as the parent compounds while the lack of a halide decreased potency, indicating the importance of Cl or F at this position. As noted above, the C3 moiety is critical for inhibition and the isopropyl group appended to the phenyl at C3 is important. Different substituents were also examined on the C3 phenyl group. Notably, the addition of a hydroxyl at the 2 position and a trifluoromethoxy group at the 5 position of the phenyl ring enhanced potency. The CDD-2847 and CDD-2902 compounds containing these changes exhibited a 10-fold increase in potency compared to the parent compounds CDD-2750 and CDD-2901. E. coli/MCR-1 grew up to a 10000-fold lower dilution on plates with colistin and 12.5 μg/ml compound compared to the colistin only control and thus display a 100-fold increase in potency compared to the hit compound CDD- 1938. CDD-2847 and CDD-2902 are the most potent antibacterial compounds identified in the SAR studies herein. - 88 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) As described above, all of the analog compounds were tested against E. coli expressing MCR-1 using the spot test shown in FIG.7. To place the spot test results in context, minimum inhibitory concentrations (MICs) were determined for a subset of the compounds including CDD-1938, CDD-2750, CDD-2901, and CDD-2847 (FIG.10). The results reveal that the spot assay is a good indicator of the relative inhibitory activity of the compounds. The colistin MIC in the absence of compounds is 4.0 μg/ml in all experiments (FIG.10). The colistin MIC is 2 μg/ml at 6.25 µM CDD-1938, 1 μg/ml at 50 μM, and 0.5 μg/ml at 100 μM compound. In contrast, for CDD-2750, which is 10-fold more potent than CDD-1938 in the spot assay, the colistin MIC is 0.125 μg/ml at 6.25 μM compound and 0.0156 μg/ml at 50 μM compound. Further, for CDD-2847, which is 100 to 1000-fold more potent than CDD-1938 in the spot assay, the colistin MIC is 0.0156 μg/ml at 6.25 μM compound and 0 µg/ml at 25 μM compound. CDD-2901 has similar MIC values as CDD- 2847 (FIG.10). Thus, as predicted by the spot assay, CDD-2847 and CDD-2901 are very potent compounds as measured by MIC. As seen in FIG.11, the most potent compound against the clinical strains is CDD- 2847, which also displayed high potency by spot and MIC versus the laboratory strain of E. coli. CDD-2847 showed a 10000-fold effect compared to the colistin only control for all of the E. coli MCR-1 clinical strains but showed a 10-fold effect versus the K. pneumoniae strain. CDD-3019, CDD-2902, and CDD-2918 also showed 100-1000x activity against the E. coli strains and 10x activity versus K. pneumoniae. CDD-3002, CDD-2750, and CDD-2901 showed progressively less activity towards E. coli and no activity against the K. pneumoniae strain. Other modifications at the C1 position were examined (FIG.9, FIG.12). CDD-3083 is CDD-2901 with a piperidine ring replacing the pyrazine ring. The spot test, however, showed CDD-3083 has no activity. Similarly, CDD-3124 is CDD-2901 with a pyrrolidine ring replacing the pyrazine but it also shows no activity in the spot test. Compounds with various substituents on the nitrogen of the pyrazine ring were examined. CDD-3259 is CDD- 2901 with a pyridine ring attached to the pyrazine nitrogen. The spot test revealed CDD-3259 retains activity but is 100-fold less potent compared to CDD-2901. CDD-3295 is CDD-2901 with a guanidinium group at the pyrazine nitrogen. Interestingly, the spot test showed this compound is only 10-fold less potent than CDD-2901 and thus shows 100x activity compared to the colistin only control. The next structure-activity relationship examined for CDD-1794, the other hit compound from the DNA-encoded libraries (FIG.6). As noted, CDD-1794 reduces the - 89 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) colistin MIC of E. coli containing MCR-1 compared to colistin alone (Tables 3-4). A summary of the SAR results is shown in FIG.13. It was found that Cl substituted at the 4- position of the benzyl ring increased potency in the spot assay. In addition, multiple analogs with changes in the linker moiety showed that increasing the linker length reduced the solubility of compound. Further, it was demonstrated that the (S) enantiomer at the cycle 2 building block position was more active than (R). Finally, after surveying multiple changes at the cycle 2 position resulted in the highest potency by the spot assay. Spot assay results showed compound CDD-3356 exhibits 100X activity compared to the colistin only control. Table 3. Minimum Inhibitory Concentration (MIC) of certain compounds E. coli containing a plasmid encoding wild-type MCR-1 Cmpd (µM) CDD-1794 CDD-1938 0 4 4 6.25 2 1 12.5 2 0.5 25 2 0.5 50 1 0.5 100 0.5 0.25 200 0.5 0.25 400 0.25 0.125 Table 4. Minimum inhibitory concentration (MIC, µg/mL) of certain compounds against E. coli containing a plasmid encoding T285A MCR-1. Cmpd (µM) CDD-1794 CDD-1938 0 >0.16 >0.16 6.25 >0.16 0.08 12.5 >0.16 0.08 25 >0.16 0.08 50 >0.16 0.08 100 >0.16 0.04 Table 5. Exemplary colistin sulfate minimum inhibitory concentration (MIC) data Cmpd Colistin sulfate MIC (µg/mL) - 90 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) concentration E. coli XL1Blue + K. pneumoniae AR E. coli XL1Blue + WT (µM) T285A MCR-1 Bank #0497 (mcr-1+) MCR-1 StrepII StrepII CDD- CDD- CDD- CD-3003 CD-3003 CD-3003 3356 3356 3356 (16) 32, (1) 2, (1) ≤0.03125, ≤0.03125, 0 32, 32 (1) 2, (1) 2 32 2 ≤0.03125 ≤0.03125 (4) 8, (8) 6.25 0.5, 0.5 ND ND ND ND 16 ≤0.03125, ≤0.03125, ≤0.03125, ≤0.03125, 12.5 0.5, 0.5 NA, 2 ≤0.03125 ≤0.03125 ≤0.03125 ≤0.03125 25 0.5, 1 (4) 8, 2 ND ND ND ND The MIC assay for K. pneumoniae used LB media, and for E. coli it used LB+ chloramphenicol (12.5 µg/mL) to maintain the plasmid carrying the wild type mcr-1 or T285A mcr-1 mutant gene. The 96-well culture plates were grown for 20.5 hrs at 35°C with 200 revolutions per minute (RPM) orbital shaking. NA: Not available, ND: Not determined, ( ): unclear if there was growth, difficult to read; data obtained using microdilution method. Table 6. Exemplary colistin sulfate minimum inhibitory concentration (MIC) data Colistin sulfate MIC (µg/mL) Compound E. coli XL1Blue + WT MCR-1 E. coli XL1Blue + T285A MCR- concentration StrepII 1 StrepII (µM) CDD- CDD- CDD- CDD- CDD- CDD- 2750 3003 2847 2750 3003 2847 0 4 4 4 0.0625 0.0625 0.03125 6.25 0.125 0.25 0.0156 0.0625 ≤0.03125 0.0156 12.5 0.125 0.125 0.0156 0.03125 ≤0.03125 0.0156 25 0.03125 0.125 0 0.0156 0.0156 0 E. coli XL1Blue expressing WT MCR-1 or T285A MCR-1 was grown in LB media and chloramphenicol (12.5 ug/mL). The 96-well culture plates were grown overnight at 37o C with 200 revolutions per minute (RPM) orbital shaking; data obtained using microdilution method. Example 6: Testing of certain exemplary compounds for cytotoxicity versus human cells Based on the cytotoxicity results, a structure-activity study was performed to reduce the toxicity of antibiotic compounds. It was hypothesized that the basicity of the secondary - 91 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) amine on the pyrazine ring may contribute to toxicity and therefore synthesized a series of morpholines with oxygen replacing the nitrogen. Table 7 summarizes the HepG2 cellular assay results. Compound CDD-3212 is a morpholine derivative of CDD-2902. However, the spot assay showed a 100-fold loss of potency compared to CDD-2902. Similarly, CDD-3213 and CDD-3239 are morpholine derivatives of CDD-2901 and CDD-3002 and the spot assay shows a >100-fold decrease in potency. Finally, CDD-3240 and CDD-3084 are morpholine derivatives of CDD-3019 and CDD-2901 but also lacking the halide. Spot assay results showed both of these compounds exhibit a >100-fold decrease in potency. Cytotoxicity assays of CDD-3084 with HepG2 cells showed low toxicity with an IC50 > 100 μM, suggesting the morpholine modification reduces cytotoxicity. Cytotoxicity tests with HepG2 cells showed an IC50 of 19 μM, indicating it is toxic. CDD-3260 is a regioisomer of CDD-3002 with respect to the position of the fluorophenyl ring on the pyrazine ring. Spot test results showed that this compound also retains 100x activity compared to the colistin only control. However, the IC50 for HepG2 cells is 19 μM, indicating toxicity may be a challenge for certain compounds. A series of compounds was synthesized wherein the nitrogen of the pyrazine ring at the C1 position was methylated (FIG.12). CDD-3035 is CDD-2901 with the pyrazine nitrogen methylated. The spot assay indicated that, although it is less potent than CDD-2901, it has 10-100X activity compared to the colistin only control. In addition, the IC50 for HepG2 cells is >100 μM, suggesting this is a candidate for further study. CDD-3003 is the methylated version CDD-3002 and the spot assay revealed it has 100x activity compared to the colistin control. The IC50 for HepG2 cells is 51 μM, indicating relatively low toxicity. CDD-3337 is the methylated version of CDD-3228 and the spot assay showed it has 100x activity compared to the colistin control. Interestingly, it has similar activity as the parent CDD-3228. Further, it displays an IC50 of >100 μM for HepG2 cells, indicating it is not toxic. CDD-3350 is the methylated version of CDD-3227, which displayed 100x activity compared to the colistin control in the spot assay. CDD-3350 also showed 100x activity relative to the colistin control. However, the IC50 of CDD-3350 for HepG2 cells is 28 μM, indicating moderate toxicity. Based on potency and toxicity, CDD-3003 and CDD-3737 are the top candidates for advancement from the CDD-1938 series. In addition, cytotoxicity assays with human HepG2 cells showed only modest toxicity for CDD-3356 with an IC50 of 53 µM. The results revealed that certain compounds of the disclosure exhibit significant cytotoxicity versus the HepG2 cells with IC50 values ranging from 14 to 21 μM (FIG.9). The compounds - 92 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) were also tested against mouse primary hepatocytes and also exhibited significant toxicity with IC50 values <10 μM. Table 7. HepG2 IC50 data for certain compounds of the disclosure. Cmpd HepG2 IC50 Cmpd HepG2 IC50 Cmpd HepG2 IC50 CDD-3003 37 – 68 µM CDD-3287 11 µM CDD-3295 19 µM CDD-3356 53 µM CDD-3062 14, 20 µM CDD-3260 19 µM CDD-2750 21 µM CDD-3350 19, 28 µM CDD-3035 >100 µM CDD-2847 10, 16 µM CDD-3366 44 µM CDD-3337 66, >100 µM CDD-2902 14 µM CDD-3368 26 µM CDD-3149 51 µM CDD-2901 16 µM CDD-3384 82, 100 µM CDD-3357 50 µM Example 7: MCR-1 is a major determinant of colistin resistance in E. coli MCR-1 plays a central role in lipid A modification in E. coli and confers colistin resistance. To show the resistance contribution of MCR-1 to E. coli, both wild type (WT) MCR-1 and a catalytically inactive mutant, T285A MCR-1, expressed from a plasmid were grown in rich media with and without colistin antibiotic over 6 hours up to 24 hours. It was shown that WT MCR-1 de-sensitizes E. coli to various concentrations of colistin, while the lack of a catalytically functional MCR-1 results in the sensitization of E. coli to colistin (FIG. 14 and FIG.22). WT and mutant strains grew similarly without antibiotics (FIG.14). Example 8: Identification of certain exemplary MCR-1 inhibitors It was hypothesized that inactivation of MCR-1 by an inhibitor co-administered with a polymyxin, such as colistin, could allow polymyxin antibiotics to more effectively kill bacteria and so identified this enzyme as a promising drug target for interfering with the plasmid-mediated polymyxin resistance mechanism. This strategy is analogous to beta- lactamase inhibitor/beta-lactam combinations that have had clinical success. Several inhibitors targeting MCR-1 have been reported in the literature, however, none demonstrate highly potent activity. To identify novel compounds with bioactivity against MCR-1, a number distinct, unbiased DNA-encoded chemical libraries consisting of a total of 2 billion compounds were screened against purified N-terminal 6xHis-tagged full-length E. coli WT MCR-1. DNA-encoded small molecule/protein complexes were captured using nickel beads - 93 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) and washed. Bound small molecules were released and bound again to fresh MCR-1 protein for two additional rounds of enrichment. After the final elution, the DNA section of the conjugates was amplified by PCR and subjected to deep sequencing. Bioinformatics analysis was used to identify the sequences most highly represented after the binding selection. Binding enrichment was observed for MCR-1 and a pair of distinct library compounds, CDD- 1938 and CDD-3358 (FIGs.15A-15B). A truncated version of compound CDD-3358 was synthesized to create CDD-1794 and tested for activity (FIG.15B). Example 9: Validation of certain exemplary MCR-1 inhibitors To validate the activity of the small molecules CDD-1938 and CDD-1794, spot assays were performed. This method provides an efficient preliminary screen to assess growth of multiple samples under various treatments simultaneously. The activity of CDD-1938 and CDD-1794 towards E. coli/MCR-1 was tested by spotting an equal volume of ten-fold serial dilutions of culture onto the surface of agar plates containing low (3.125 ^M), medium (6.25 ^M), and high (12.5 ^M) concentrations of inhibitor with or without a sub-inhibitory concentration of colistin methane sulfonate (CMS) (0.32 ^g/mL) followed by overnight growth at 37°C. CMS was used to prepare the plates, which were made the day before to allow for complete hydrolysis of CMS to colistin. After incubation, viability was visually assessed based on the appearance of a bacterial lawn or colonies within the spots with lack of growth as the endpoint. The spot assay results showed CDD-1938 and CDD-1794 reduced the growth of E. coli/MCR-1 in combination with colistin (FIG.16A). The presence of increasing concentrations of CDD-1938 resulted in progressively greater susceptibility of E. coli/MCR-1; however, a dose-dependent susceptibility was not observed for the concentrations of CDD-1794 tested. To score the spot assays, the viability of E. coli/MCR-1 and E. coli/T285A on control and test plates was evaluated. For example, on the plates containing the highest inhibitor concentration (12.5 ^M) and 0.32 ^g/mL colistin, E. coli/MCR-1 grew to a 10-fold lower dilution compared to growth on plates containing 0.32 ^g/mL colistin with no inhibitor (FIG.16A). This difference in growth between treatments was scored as a 10X effect for the inhibitors CDD-1938 or CDD-1794, which showed similar results. It was confirmed that MCR-1 was the target of the compounds by testing against E. coli with the catalytically inactive MCR-1 T285A mutant, where the expression of the mutant MCR-1 fails to protect E. coli from colistin. Unlike with E. coli/MCR-1, no effect of the compounds was observed in combination with colistin against E. coli/MCR-1 T285A, - 94 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) demonstrating that CDD-1938 and CDD-1794 activity is focused on disrupting a functional MCR-1. The no antibiotic control showed equal growth of the E. coli/MCR-1 and E. coli/T285A strains indicating that the presence of high concentrations of inhibitor alone does not inhibit E. coli growth (FIG.16A). The compounds were further validated for activity by determining colistin sulfate minimum inhibitory concentrations (MIC) against E. coli/MCR-1 and E. coli/ MCR-1 T285A. This experiment was performed by determining the MIC for colistin in the presence of increasing concentrations of compounds CDD-1938 and CDD- 1794 (no antibiotic and inhibitor controls were included), showing that the colistin MIC was reduced between 2-32X, depending on the inhibitor concentration, consistent with inhibition of MCR-1 (FIG.16B). Notably, a dose-dependent growth reduction of E. coli/MCR-1 by CDD-1794 combined with colistin was observed for the wider concentration range (0-100 ^M) used in the MIC assay, indicating that CDD-1794, like CDD-1938, also reduces growth in a dose-dependent manner although it requires a higher concentration to do so (FIG.16B). A colistin/compound effect was not observed for E. coli/ MCR-1 T285A, further supporting the hypothesis that CDD-1938 and CDD-1794 target a catalytically active MCR-1. It was also determined the effect of the compounds on the growth of E. coli/MCR-1 and E. coli/ MCR-1 T285A in the absence of colistin and found the compounds had no effect on the bacterial growth rate. Example 10: Optimization and prioritization of certain exemplary chemotype I MCR-1 inhibitors The development of compounds that inhibit MCR-1 and show bioactivity in the 1 ^g/mL range in the colistin MIC assay were sought. These potencies would compare favorably with the potencies observed for beta-lactamase inhibitors in clinical use. Using preliminary medicinal chemistry to explore structure-activity relationships (SAR) and enhance the potency of the compounds, analogs of CDD-1938 and CDD-1794 were synthesized and tested for bioactivity as described above. The SAR approach focused on modifying and testing the DECL cycle building blocks for each compound; in this case, both chemotype CDD-1938 and CDD-1794 consisted of three cycle building blocks (BB) each, which were designated as C1 BB, C2 BB and C3 BB (FIGs.15A-15B). Compound CDD-1938 is a racemic mixture with a chiral center at the phenyl substitution on the piperazine ring on the C1 BB (FIG.15A). Both enantiomers were synthesized and tested for activity. E. coli/MCR-1 treated with colistin and the R- - 95 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) enantiomer, CDD-2778, showed no change in potency compared to CDD-1938, and E. coli/MCR-1 on plates with colistin and 12.5 ^M of the S-enantiomer, CDD-2748, also did not show a detectable difference in potency compared to CDD-1938, indicating that both the R- and S-enantiomers show similar potency to the racemic mixture (FIG.26). The R- enantiomer was advanced for further SAR. It was next tested whether the benzylamide- containing moiety that served as a linker to the DNA contributes to potency by removing this group to generate CDD-2750 (FIG.15C). E. coli/MCR-1 grew to a 100-1000-fold lower dilution on plates containing colistin with 12.5 ^M compound compared to the colistin-only control, indicating that the removal of this linker results in a 10-100-fold improved inhibitory activity against MCR-1 compared to CDD-2778 (FIG.26) and a 100-fold increase in bioactivity compared to CDD-1938 (FIG.17). The contribution of the isopropyl phenyl in the C3 BB was also tested by synthesizing CDD-2932, which lacks the C3 group (FIG.26). Removal of this group resulted in a 100-fold decrease in potency in the spot assay compared to the CDD-2750 parent compound, indicating the C3 group contributes significantly to MCR-1 inhibition (FIG.26). CDD-2889, which retains the C3 phenyl, but lacks the isopropyl group also showed a 100-fold loss in potency relative to the CDD-2750 parent, demonstrating the importance of the isopropyl group for MCR-1 inhibition (FIG.26). Both CDD-1938 and its more potent analog, CDD-2750, contain a halide appended to the phenyl group at the C1 BB (FIG.15A and FIG.15C). CDD-2835 is CDD-2750 lacking the halide (FIG.26). This compound showed a 100-fold loss in potency relative to CDD-2750, revealing the importance of the halide for inhibitor bioactivity. The chlorine in CDD-2750 was also replaced with fluorine to create CDD-3228, which exhibited similar potency in the spot assay as CDD-2750 (FIG.26). In brief, the absence of the linker improved the potency of the inhibitor, and the stereochemistry of the chiral carbon of the piperazine ring did not noticeably impact inhibitor potency. Next was assessed the impact of substituting the nitrogen in the pyridine ring in the C2 BB. The pyridine ring in CDD-2750 was replaced with a benzyl ring to create CDD-2901 (FIG.15C) and the spot assay showed no change in potency against E. coli/MCR-1, suggesting the nitrogen was not important for inhibition (FIG.17). The Cl was substituted by an F in CDD-2901, which possesses a benzyl rather than a pyridine ring at C2, to create CDD-3002 (FIG.17C). CDD-3002 displayed similar potency to CDD-2901 based on the spot assay (FIG.17). Thus, both F-containing compounds, CDD-3228 (FIG.26) and CDD- 3002 (FIG.15C), showed similar bioactivity as the parent Cl-containing compounds while - 96 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) the elimination of a halide reduced potency, suggesting that Cl and F are important at this position. As previously noted, the C3 BB is essential for inhibition and the isopropyl group appended to the phenyl of C3 BB is a key substituent. The addition of different substituents on the C3 phenyl group was further investigated. Addition of a hydroxyl group at the 2- position and a trifluoromethoxy group at the 5-position contributed a notable improvement in potency. The CDD-2847 and CDD-2902 compounds carrying these modifications displayed a 10-fold increase in potency compared to their parent compounds, CDD-2750 and CDD- 2901, respectively (FIG.17). E.coli/MCR-1 grew to 10,000-fold lower dilution on plates with colistin and 12.5 ^M compound compared to the colistin-only control and therefore exhibit 100-fold improved potency compared to the original hit compound, CDD-1938. CDD-2847 and CDD-2902 are the most potent compounds that were identified in the SAR studies for chemotype CDD-1938. It was hypothesized that addition of a hydroxyl at the 2- position and trifluoromethoxy at the 5-position of the C3 BB phenyl enhanced bioactivity over the isopropyl alone, and thus, two additional analogs were prepared comprising the -OH and -OCF3 and the C2 BB was modified by adding a methyl to create CDD-2918 and the C1 BB was modified by substituting the halide from Cl to F to create CDD-3019. Both compounds maintained an equivalent potency to the CDD-2902 parent and were still 10X more potent than CDD-2901 (FIG.26). As noted above, all the compounds were tested against E. coli/MCR-1 as well as E. coli/T285A MCR-1 using the spot assay. To further validate the spot assay results, colistin MIC assays were performed for a subset of the most potent compounds including CDD-1938, CDD-2750, CDD-2901, and CDD-2847 (FIGs.18A-18B). The results confirmed that the spot assay is a good indicator of the relative inhibitory activity of the compounds. When comparing the compounds between assays, the results show similar changes in potency between compounds relative to one another although the scoring/quantitation of the assay endpoints differ. Hence, as predicted by the spot assay, CDD-2847 and CDD-2901 are very potent compounds as also measured by MIC (FIGs.18A-18B). Example 11: Activity of certain exemplary chemotype 1 MCR-1 inhibitors against colistin resistant clinical isolates The spot assay was next used to examine the activity of a subset of compounds against a set of five clinically relevant isolates that were obtained from the CDC & FDA Antibiotic Resistance Isolate Bank. These isolates include MDR strains that are validated for - 97 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) the presence of the MCR-1 or MCR-2 colistin resistance genes. The MCR-2 variant shares 81% amino acid identity with MCR-1. One Klebsiella pneumoniae and four E. coli strains were tested using spot assays with 0.32 µg/mL CMS and 12.5µM compound (FIG.19). A total of seven chemotype 1 compounds were evaluated including CDD-2901, CDD-2750, CDD-3002, CDD-2918, CDD-2902, CDD-3019 and CDD-2847. All of these compounds had been shown to have significant activity in the spot assay (^100X) (FIG.17 and FIG.26) and, for some, by MIC against E. coli/MCR-1 (FIGs.18A-18B). As seen in FIG.19, the most potent compound against clinical strains is CDD-2847, which also displayed the highest potency by spot and MIC versus the E. coli/MCR-1 laboratory strain. CDD-2847 showed a 10,000-fold effect compared to the colistin only control for all the E. coli/MCR-1 clinical strains; however, it exhibited a 10-fold effect against the K. pneumoniae strain. Without wishing to be bound by any theory, this may be due to its difficult-to-permeate capsule and the presence of efflux pumps such as the OqxA pump. The low sub-inhibitory concentration of colistin at 0.32 µg/mL, in combination with the inhibitor, may also affect its efficacy in killing K. pneumoniae. It is hypothesized that killing will be more effective when colistin concentration is increased. CDD-3019, CDD-2902 and CDD-2918 also showed >1000-fold activity against all five of the E. coli clinical strains, and CDD-3019 and CDD-2902 showed 10-fold activity versus K. pneumoniae. CDD-3002, CDD-2750 and CDD-2901 displayed progressively less activity towards E. coli and no activity against the K. pneumoniae strain. Of note, these three latter compounds have an isopropyl on the C3 BB compared to the C3 BB on the former three compounds, which possess the -OH and -OCF3 combination. In general, these compounds displayed potent activity against E. coli clinically relevant strains, but to a lesser degree against K. pneumoniae clinical isolates. Initially, CDD-2750, in combination with colistin, was tested, as described above, against seven E. coli clinical isolates (Colombia) validated for the presence of MCR-1. CDD-2750/colistin exhibited a 100-1000X inhibitory effect against four of the seven E. coli strains indicating the inhibitor enhanced colistin killing over colistin alone (FIG.23). Example 12: Cytotoxicity profile of certain exemplary chemotype 1 MCR-1 inhibitors The potential for cytotoxicity was examined by testing a set of potent compounds including CDD-2750, CDD-2901, CDD-2847 and CDD-2902 against the human HepG2 cell line. The viability assays revealed that the compounds show significant cytotoxicity against the HepG2 cells with IC50 values ranging from 14-21^M (Table 8). Primary human - 98 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) hepatocytes (PHHs) were also used to evaluate metabolism-associated drug toxicity of CDD- 2750 and CDD-2847; the viability results indicated significant cytotoxicity against PHHs with an IC50 of 9 ^M consistent with the HepG2 results (Table 8). The compounds were also tested against primary mouse hepatocytes and exhibited significant toxicity with IC50 values <10 ^M (Table 8). Table 8. Cytotoxicity of enhanced potency MCR-1 inhibitors measured against human and mouse hepatocytes IC50 (µM) Compound Primary human Primary mouse HepG2 hepatocytes hepatocytes hepatocytes CDD-2750 21.41 8.63 <10 CDD-2901 15.85 ND <10 CDD-2847 15.63 9.81 <10 CDD-2902 14.02 ND <10 Compounds were incubated at different concentrations (0-100 µM) with human HepG2 and primary human hepatocytes and incubated at room temperature for 24 hours. Viability of cells was determined using the CellTiterGlo assay. Primary human hepatocytes (PHH) were cryopreserved, 100-donor mixed gender. Primary mouse hepatocytes [fresh/cryopreserved??] were incubated at 37°C and assessed for viability at 24 hours post treatment (n = 4). ND, not determined. Example 13: Structure-activity studies to reduce toxicity and maintain potency Based on the results described elsewhere herein, additional structure-activity studies were performed to reduce the cytotoxicity of the compounds. It was hypothesized that the basicity of the secondary amine on the piperazine ring contributes to the toxicity and therefore a series of morpholines were synthesized with oxygen replacing the nitrogen at position 1 (FIG.26). Compound CDD-3212 is a morpholine derivative of CDD-2902 (FIG. 26). However, the spot assay showed a 10,000-fold loss of potency compared to CDD-2902. Similarly, CDD-3213 and CDD-3239 are morpholine analogs of CDD-2901 and CDD-3002 (FIG.26) and the spot assay revealed a >100-fold reduction in potency (FIG.26). Finally, compound CDD-3240, a morpholine derivative of CDD-2902 with the exception that the - OH and -OCF3 substituents are flipped in position on the C3 BB and the chlorine is substituted for a F on the C1 BB, and compound CDD-3084, a morpholine derivative of CDD-2901, which lacks a halide on the C1 BB, were synthesized. Spot assay results showed both compounds display a >100-fold decrease in potency, suggesting the secondary amine is - 99 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) important for activity, which is consistent with the spot assay findings for all the other morpholine derivatives. Interestingly, CDD-3240 in combination with colistin was the only morpholine derivative to show some potency compared to the colistin-only control. This is likely due to the activity imparted by the -OH and -OCF3 on the C3 BB phenyl. Cytotoxicity assays of CDD-3084 with HepG2 cells showed low toxicity with an IC50 > 100 ^M, indicating the morpholine modification reduces cytotoxicity (FIG.26); however, potency was lost and thus, the morpholine analogs were eliminated as candidates. Other modifications on the C1 BB were also assessed. CDD-3083 is CDD-2901 with a piperidine ring replacing the piperazine ring (FIG.26). The spot test results showed the ring substitution in CDD-3083 led to loss of potency, suggesting the substitution of the nitrogen at the 1 position with a carbon is not well tolerated with respect to inhibitor potency, like the oxygen in the morpholine analogs. Similarly, CDD-3124 is CDD-2901 with a pyrrolidine ring in place of the piperazine, and it showed no activity in the spot test (FIG.26), indicating the presence of a nitrogen in this N1 position is important for activity. Compounds with various substituents on the nitrogen at position 1 of the piperazine ring were also evaluated. CDD-3259 is CDD-2901 with a pyridine ring attached to the piperazine nitrogen (FIG.26). The spot assay showed CDD-3259 retains some activity but is 100-fold less potent compared to CDD-2901. CDD-3295 is CDD-2901 with a guanidine group at the piperazine N1 (FIG.26). The spot assay results showed that the addition of this substituent decreases potency by 10-fold compared to CDD-2901 but is still 100-fold more active versus the colistin-only control (FIG.26), and its cytotoxicity tests against HepG2 cells exhibited an IC50 of 19 ^M, indicating it is toxic. CDD-3260 is CDD-3002 with the fluorobenzene ring at the 2-position of the piperazine ring rather than the 1-position (FIG.26). This substitution caused a >10 reduction in activity and was toxic based on the IC50 of 19 ^M for HepG2 cells, supporting the idea that the basicity of a free piperazine secondary amine contributes to toxicity. Based on the hypothesis that cytotoxicity originates from the nitrogen at position 1 or 4 of the piperazine ring, a methyl group was added to N1 of the piperazine ring on CDD-2901 to create CDD-3035 (FIG.26). The spot assay showed CDD-3035 is 10- to 100-fold more active than the colistin-only control, but it was 10-fold less active than its parent compound. However, the IC50 of CDD-3035 for HepG2 cells was >100 ^M, indicating that methylation of the piperazine N1 greatly reduces cytotoxicity. Considering this, the methylated N1 substitution was held constant and additional analogs were generated which explored changes - 100 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) in the C2 group to enhance potency. CDD-3003 (FIG.15C) is the methylated version of CDD-3002 (FIG.15C) and the spot assay showed it has 100-fold activity compared to the colistin-only control (FIG.17) The IC50 for CDD-3003 for HepG2 cells is 64 ^M, indicating relatively low toxicity. CDD-3337 (FIG.26) is the methylated version of CDD-3228 (FIG. 26) and the spot assay results revealed it has 10-100-fold activity compared to the colistin- only control. Notably, it has similar activity to CDD-3228. Further, it exhibits an IC50 >100 ^M for HepG2 cells, indicating it is not toxic. CDD-3350 (FIG.26) is CDD-3337 with -OH and -OCF3 instead of isopropyl on C3 BB, which displayed 1000-fold activity relative to the colistin-only control in the spot assay. However, the IC50 of CDD-3350 for HepG2 cells is 28 ^M, pointing to moderate toxicity and suggesting the -OH and -OCF3 on the C3 BB play a role in toxicity. Based on the potency and toxicity results, CDD-3003 was selected as the lead candidate for the chemotype CDD-1938 series. Example 14: Optimization and prioritization of MCR-1 chemotype 2 lead inhibitors Next, the SAR approach was focused on chemotype 2 MCR-1 inhibitors to identify more bioactive analogs belonging to this chemotype. The original DECL hit for CDD-3358 contained a DNA molecule attached via a linker to the C1 BB. The C2 and C3 substituents branch from the C1 BB. Initially, a truncated version of CDD-3358 was synthesized to create CDD-1794, which lacks the DNA linker, ethyl cyclopentane of the C2 group and halide appended to the C3 phenyl group. Focus was placed on modification of CDD-1794, which in combination with colistin exhibits activity against E. coli/MCR-1 in the spot and MIC assays (FIGs.16A-16B). To confirm the importance of the C2 group, the ethyl benzene was eliminated from CDD-1794 to create CDD-2797, which resulted in a 10-fold loss in potency relative to CDD-1794, suggesting an important role for the ethyl benzene for activity (FIG. 27). The reduction of activity observed for CDD-2797 was able to be rescued by adding a chlorine at the 4-position of the benzene ring of the C3 group to create CDD-2832 (FIG.27). The latter analog displayed the same potency as CDD-1794 based on the spot assay, indicating chlorine plays an important role in the inhibitory activity of CDD-2832 (FIG.27). However, adding an ethyl benzene to CDD-2832, as present in CDD-1794, to create CDD- 2833 did not change the bioactivity of the inhibitor compared to CDD-2833 suggesting that Cl and the ethyl benzene may be interchangeable with respect to potency (FIG.27). Based on these data, it was decided that the Cl of CDD-2832 would be maintained and exploration of the role of the C2 group would be continued by substituting and/or adding different - 101 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) substituents to the C1 BB. Using the parent compound CDD-2832, CDD-3359 was synthesized to examine the effect of the addition of an ethyl indole to the C1 BB. E. coli/MCR-1 grew to a 10-fold lower dilution on plates containing colistin with 12.5^M of CDD-3359 compared to the colistin-only control, indicating that this addition results in no change to potency compared to CDD-2832 or CDD-1794 (FIG.27). Next was examined a different addition—a chiral ethylnaphthalene at the C1 BB of CDD-2832 to create CDD-3367. This analog is an S-enantiomer, and it also did not show any change in potency compared to CDD-2832 nor CDD-1794 based on the spot assay (FIG. 27). To further explore the impact of stereochemistry at the chiral center of a substituent at the C1 BB, CDD-3357 was synthesized by attaching an ethyl methyl trifluoromethyl benzene ring to the C1 BB in the R-configuration. CDD-3357 showed a similar potency to CDD-3367 (FIG.27). It is unclear if this result indicates that stereochemistry at the chiral center of the two substituents does not matter or if it is the result of the size and nature of the substituents. To evaluate the activity of a larger branched C2 group, a cyclopropane ring was added to the CH2 of the benzyl ring in CDD-2833 to produce CDD-3356 (FIG.15D), which is an S- enantiomer with a chiral center at the CH2 of the benzyl substituent on the C1 BB. Notably, this addition increased the potency of the inhibitor by 10-fold compared to CDD-2833 (FIG. 27) or any of the other inhibitors tested, suggesting the addition of cyclopropane enhances potency in conjunction with the benzyl ring. This expanded chemical space at the C2 BB may increase the permeability characteristics of the inhibitor or improve binding to MCR-1. The specificity of the cyclopentane in that position (FIG.15D) was tested by substituting it with an ethyl methoxy, a small aliphatic side chain, to create CDD-3366. The spot assay showed no change in potency against E. coli/MCR-1 for CDD-3366, a racemic mixture, in combination with colistin, suggesting that either side chain contributes equally to inhibition. Next, further studies were considered for CDD-3356, because time-kill curve (TKC) data showed a more rapid and pronounced inhibition of growth of E. coli/MCR-1 by the colistin/CDD-3356 treatment compared to the colistin/CDD-3366 treatment (FIGs.24A- 24B). Moreover, cytotoxicity assays with human HepG2 cells displayed only modest toxicity for CDD-3356 with an IC50 of 53 ^M versus 44 ^M for CDD-3366, and it is difficult to synthesize the S- and R-enantiomers of CDD-3366. The Cl in CDD-3356 was replaced with an F to create CDD-3682, which exhibited a slight decrease in potency in the spot assay compared to CDD-3356, indicating that Cl exhibits improved activity at the 4-position of the C3 phenyl ring. Next was examined the contribution of a primary, secondary or tertiary - 102 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) amide appended to the C1 benzimidazole ring. Replacing the secondary amide on the C1 group of CDD-3356 with a tertiary amide to create CDD-3633 resulted in a modest loss of potency as indicated on the spot assay, and replacing the secondary amide on the C1 group of CDD-3356 with a primary amide to create CDD-3364 resulted in a 10-fold loss in potency in the spot assay. These data suggest the secondary amide at the C1 group of CDD-3356 provides the best inhibitor potency. Replacing the secondary amide with a primary amide (CDD-3636) or tertiary amide (CDD-3635) in the CDD-3366 compound (the C2 group contains an ethyl methoxy in place of the cyclopropane) resulted in the same order of loss of bioactivity as the replacements for CDD-3356, suggesting the secondary amide is important for potency independent of the ethyl methoxy or cyclopropane substituent at the C2 group. Substitution of the C7 in the benzimidazole ring to a N in CDD-3356 to create CDD-3638 was also performed, which resulted in a 10-fold loss of bioactivity against E. coli/MCR-1, indicating the importance of preserving a carbon at the C7 position. Based on potency and toxicity, CDD-3356 is a lead candidate for the CDD-1794-related (chemotype 2) series. Example 15: Activity of certain exemplary lead MCR-1 inhibitors against colistin resistant Klebsiella pneumoniae The MIC assay was used to examine the activity of CDD-3356 and CDD-3003 (Table 9) versus a colistin resistant clinical strain of Klebsiella pneumoniae known to contain mcr-1 and a laboratory strain of E. coli expressing WT MCR-1 or catalytically inactive T285A MCR-1. MIC assays were performed by broth microdilution with 2-fold dilutions of colistin sulfate antibiotic and 0, 6.25, 12.5 and 25 ^M compound. The colistin MIC for mcr-1+ K. pneumoniae was 8 ^g/mL. However, when 12.5 ^M or greater concentration of CDD-3356 was combined with colistin, the colistin MIC was reduced by 16-fold to 0.5 ^g/mL (Table 9), indicating that the inhibitor blocks the colistin resistance mechanism encoded by mcr-1. CDD-3003 was also able to reduce the colistin MIC, but less so with an 8-fold reduction at 12.5 ^M (Table 9). Based on the MIC data, CDD-3356 displays progressively more activity against K. pneumoniae mcr-1+ as its concentration increases when combined with colistin. For colistin/CDD-3003, an abrupt change in colistin MIC occurs at 12.5^M, but not at lower inhibitor concentrations. Four-fold less CDD-3356 is needed to re-sensitize K. pneumoniae mcr-1+ at an equivalent level compared to CDD-3003 suggesting CDD-3356 is the more potent inhibitor against this isolate. K. pneumoniae is encapsulated and contains the efflux pump oqxA gene; nevertheless, certain lead compounds of the disclosure can penetrate - 103 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) the cell and effectively reduce bacterial growth. The MIC endpoints were lower for the laboratory strains expressing MCR-1, where 12.5 ^M CDD-3356 and CDD-3003 both reduce colistin MIC by 64X in the E. coli/MCR-1 cultures and cause no change in the E. coli/T285A strain (Table 9). These data show that two optimized chemotype leads effectively reduce K. pneumoniae clinical isolate growth, which contrasts with the less potent activity profile of initial chemotype 1 compounds observed in FIG.17. Table 9. Optimized inhibitors resensitize a Klebsiella pneumoniae clinical isolate and laboratory E. coli carrying wildtype MCR-1 in a dose-dependent manner to colistin killing Colistin sulfate MIC (µg/mL) Cmpd K. pneumoniae AR E. coli XL1Blue + WT E. coli XL1Blue + concentration Bank #0497 (mcr-1+) MCR-1 T285A MCR-1 (µM) CDD- CDD- CDD- CDD- CDD- CDD- 3356 3003 3356 3003 3356 3003 0 8 8 4 4 0.125 0.125 1.56 2 8 0.25 0.5 ≤ 0.0625 ≤ 0.0625 3.125 1 8 0.25 0.25 ≤ 0.0625 ≤ 0.0625 6.25 1 8 ≤ 0.0625 0.25 ≤ 0.0625 ≤ 0.0625 12.5 0.5 1 ≤ 0.0625 ≤ 0.0625 ≤ 0.0625 ≤ 0.0625 25 0.5 1 ≤ 0.0625 ≤ 0.0625 ≤ 0.0625 ≤ 0.0625 Colistin sulfate MIC using the microdilution method was determined for K. pneumoniae using cation-adjusted Mueller-Hinton broth, and for E. coli using cation-adjusted Mueller Hinton broth + chloramphenicol (12.5µg/mL) to maintain the plasmid carrying the wild type mcr-1 or the catalytically inactive T285A mcr-1 mutant gene as a control. The MIC assays were performed in 96-well culture plates which were grown for 20 hrs at 35°C. Example 16: Treatment of log phase E. coli/MCR-1 cultures with colistin and certain exemplary lead inhibitor combinations The bactericidal activity of CDD-3003 and CDD-3356 in combination with colistin was examined by time-kill curves (TKC) for a more complete understanding of the rate and extent of killing E.coli/MCR-1. The colistin at 2X MIC (4 ^g/mL) and CDD-3003 (12.5 ^M) combination treatment caused a rapid reduction in colony forming units (CFU) of E. coli/MCR-1 (5-log10 in 1 hour) compared to colistin-only, which resulted in an equal decline in CFUs but at 5 hours (FIG.20A). However, this improved bactericidal effect is reduced by using less CDD-3003 inhibitor. At 4 ^g/mL colistin and 6.25 ^M CDD-3003, bacterial - 104 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) growth ends at 4 hours, while killing occurs at 5 hours post-treatment with 4 ug/mL colistin and 3.125 or 1.56 ^M CDD-3003 (FIG.20A). Complete killing of E. coli/MCR-1 with the combination treatment occurs by 1.5 hours for CDD-3356 when using 12.5 ^M of the compound, which is at least 2.5 hours before killing occurs with colistin alone. Colistin with CDD-3356 concentrations of 1.56 ^M through 6.25 ^M show varying inhibitory effects with killing between 3 and 4 hours (FIG.20B). The TKC data support that CDD-3003 and CDD- 3356 achieve a similar killing endpoint for E. coli/MCR-1 as seen in the spot assay (FIG.17). A similar response was observed in the colistin MIC results for the K. pneumoniae mcr-1+ strain in the presence of CDD-3003 or CDD-3356 (Table 9). Enumerated Embodiments The following enumerated embodiments are provided, the numbering of which is not to be construed as designating levels of importance: Embodiment 1 provides a compound of Formula (I), or a salt, solvate, stereoisomer, or isotopologue thereof: , wherein: R1 is selected from the group consisting of optionally substituted C6-C10 aryl and optionally substituted C2-C8 heteroaryl; R2a, R2b, R2c, R2d, R2e, R2f, R2g, R2h, R2i, R2j, R2k, and R2l, if present, are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 heteroalkyl, halogen, CN, NO2, ORA, N(RA)(RB), C(=O)ORA, and C(=O)N(RA)(RB), wherein two geminal substituents selected from R2a, R2b, R2c, R2d, R2e, R2f, R2g, R2h, R2i, R2j, R2k, and R2l can combine with the carbon atom to which they are bound to form C(=O); and wherein one of R2b and R2c is R3; R3 is optionally substituted C6-C10 aryl; L1 is selected from the group consisting of a bond and -C(R2g)(R2h)-; L2 is selected from the group consisting of a bond and -C(R2i)(R2j)-; - 105 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) X1 is selected from the group consisting of -N(R4)-, -O-, and -C(R2k)(R2l)-; R4, if present, is selected from the group consisting of H, optionally substituted C1-C6 alkyl, C(=O)RA, C(=O)ORA, C(=O)N(RA)(RB), C(=NRA)N(RB)(RC), optionally substituted C6-C10 aryl, and optionally substituted C2-C8 heteroaryl; and each occurrence of RA, RB, and RC, if present, is selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 heteroalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C6-C10 aryl, and optionally substituted C2-C8 heteroaryl. Embodiment 2 provides the compound of Embodiment 1, wherein the compound of Formula (I) is selected from the group consisting of: , . the compound of Formula (I) is selected from the group consisting of: R4 2), 2). R1 is selected from the group consisting of: - 106 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) , wherein R5a, R5b, R5c, R5d, selected from the group consisting of H, halogen, , substituted C1-C6 alkyl, optionally substituted C6-C10 aryl, and optionally substituted C2-C10 heteroaryl. Embodiment 5 provides the compound of Embodiment 4, wherein at least one of R5a, R5b, R5c, R5d, and R5e is phenyl, optionally wherein the phenyl is substituted with at least one selected from the group consisting of OH, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkyl, and C1-C6 haloalkyl. Embodiment 6 provides the compound of Embodiment 4 or 5, wherein R5a, R5b, R5c, R5d, and R5e, if present, are each independently selected from the group consisting of H, CH3, . 6, wherein each of the following apply: (a) R5b, R5c, and R5d, if present, are each independently H or CH3; (b) one of R5a and R5e is selected from the group consisting , (c) Embodiment 8 provides the compound of any one of Embodiments 1-7, wherein R1 is , - 107 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) R3 , wherein R6a, R6b, R6c, R6d, and R6e are selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 haloalkyl, optionally substituted C6-C10 aryl, optionally substituted C2-C10 heteroaryl, halogen, CN, NO2, ORA, N(RA)(RB), C(=O)N(RA)(RB), C(=O)RA, C(=O)ORA, and S(=O)2N(RA)(RB). Embodiment 10 provides the compound of Embodiment of 9, wherein R6a, R6b, R6c, R6d, and R6e are each independently selected from the group consisting of H, F, and Cl, optionally wherein one of R6a, R6b, R6c, R6d, and R6e is F or Cl. Embodiment 11 provides the compound of any one of Embodiments 1-10, wherein R3 is selected from the group consisting , . 12 provides the compound of a 4 ny one of Embodiments 1-11, wherein R is selected from the group consisting of H, Me, C(=NH) , and . 13 provides the compound of any one of Embodiments 1-12, which is selected from the group consisting of: 4-(3-(4-chlorophenyl)-4-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)piperazine-1- carbonyl)-N-methylbenzamide; - 108 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) (S)-4-(3-(4-chlorophenyl)-4-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)piperazine-1- carbonyl)-N-methylbenzamide; (R)-4-(3-(4-chlorophenyl)-4-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)piperazine- 1-carbonyl)-N-methylbenzamide; 2-(4-fluorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-4-methylpiperazine; (S)-2-(4-fluorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-4- methylpiperazine; (R)-2-(4-fluorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-4- methylpiperazine; 2-(4-chlorophenyl)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)piperazine; (S)-2-(4-chlorophenyl)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)piperazine; (R)-2-(4-chlorophenyl)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)piperazine; 3-(4-((2-(4-chlorophenyl)piperazin-1-yl)methyl)pyridin-3-yl)-4- (trifluoromethoxy)phenol; (S)-3-(4-((2-(4-chlorophenyl)piperazin-1-yl)methyl)pyridin-3-yl)-4- (trifluoromethoxy)phenol; (R)-3-(4-((2-(4-chlorophenyl)piperazin-1-yl)methyl)pyridin-3-yl)-4- (trifluoromethoxy)phenol; 2'-((2-(4-chlorophenyl)piperazin-1-yl)methyl)-6-(trifluoromethoxy)-[1,1'-biphenyl]-3- ol; (S)-2'-((2-(4-chlorophenyl)piperazin-1-yl)methyl)-6-(trifluoromethoxy)-[1,1'- biphenyl]-3-ol; (R)-2'-((2-(4-chlorophenyl)piperazin-1-yl)methyl)-6-(trifluoromethoxy)-[1,1'- biphenyl]-3-ol; 2'-((2-(4-fluorophenyl)piperazin-1-yl)methyl)-6-(trifluoromethoxy)-[1,1'-biphenyl]-3- ol; (S)-2'-((2-(4-fluorophenyl)piperazin-1-yl)methyl)-6-(trifluoromethoxy)-[1,1'- biphenyl]-3-ol; (R)-2'-((2-(4-fluorophenyl)piperazin-1-yl)methyl)-6-(trifluoromethoxy)-[1,1'- biphenyl]-3-ol; 2-(4-fluorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; (S)-2-(4-fluorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; (R)-2-(4-fluorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; 2-(4-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; - 109 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) (S)-2-(4-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; (R)-2-(4-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; 2'-((2-(3-chlorophenyl)piperazin-1-yl)methyl)-6-(trifluoromethoxy)-[1,1'-biphenyl]-3- ol; (S)-2'-((2-(3-chlorophenyl)piperazin-1-yl)methyl)-6-(trifluoromethoxy)-[1,1'- biphenyl]-3-ol; (R)-2'-((2-(3-chlorophenyl)piperazin-1-yl)methyl)-6-(trifluoromethoxy)-[1,1'- biphenyl]-3-ol; 2-(4-chlorophenyl)-1-((2'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)methyl)piperazine; (S)-2-(4-chlorophenyl)-1-((2'-(trifluoromethyl)-[1,1'-biphenyl]-2- yl)methyl)piperazine; (R)-2-(4-chlorophenyl)-1-((2'-(trifluoromethyl)-[1,1'-biphenyl]-2- yl)methyl)piperazine; 3-(4-((2-(4-fluorophenyl)-4-methylpiperazin-1-yl)methyl)pyridin-3-yl)-4- (trifluoromethoxy)phenol; (S)-3-(4-((2-(4-fluorophenyl)-4-methylpiperazin-1-yl)methyl)pyridin-3-yl)-4- (trifluoromethoxy)phenol; (R)-3-(4-((2-(4-fluorophenyl)-4-methylpiperazin-1-yl)methyl)pyridin-3-yl)-4- (trifluoromethoxy)phenol; 2'-((2-(4-chlorophenyl)piperazin-1-yl)methyl)-5'-methyl-6-(trifluoromethoxy)-[1,1'- biphenyl]-3-ol; (S)-2'-((2-(4-chlorophenyl)piperazin-1-yl)methyl)-5'-methyl-6-(trifluoromethoxy)- [1,1'-biphenyl]-3-ol; (R)-2'-((2-(4-chlorophenyl)piperazin-1-yl)methyl)-5'-methyl-6-(trifluoromethoxy)- [1,1'-biphenyl]-3-ol; 2'-((2-(4-fluorophenyl)-4-methylpiperazin-1-yl)methyl)-6-(trifluoromethoxy)-[1,1'- biphenyl]-3-ol; (S)-2'-((2-(4-fluorophenyl)-4-methylpiperazin-1-yl)methyl)-6-(trifluoromethoxy)- [1,1'-biphenyl]-3-ol; (R)-2'-((2-(4-fluorophenyl)-4-methylpiperazin-1-yl)methyl)-6-(trifluoromethoxy)- [1,1'-biphenyl]-3-ol; 2-(4-fluorophenyl)-4-methyl-1-((2'-(trifluoromethyl)-[1,1'-biphenyl]-2- yl)methyl)piperazine; (S)-2-(4-fluorophenyl)-4-methyl-1-((2'-(trifluoromethyl)-[1,1'-biphenyl]-2- - 110 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) yl)methyl)piperazine; (R)-2-(4-fluorophenyl)-4-methyl-1-((2'-(trifluoromethyl)-[1,1'-biphenyl]-2- yl)methyl)piperazine; 2-(3-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; (S)-2-(3-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; (R)-2-(3-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; 2-(2-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; (S)-2-(2-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; (R)-2-(2-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; 2'-((2-(4-fluorophenyl)piperazin-1-yl)methyl)-6-(trifluoromethoxy)-[1,1'-biphenyl]-3- ol; (S)-2'-((2-(4-fluorophenyl)piperazin-1-yl)methyl)-6-(trifluoromethoxy)-[1,1'- biphenyl]-3-ol; (R)-2'-((2-(4-fluorophenyl)piperazin-1-yl)methyl)-6-(trifluoromethoxy)-[1,1'- biphenyl]-3-ol; 2-(4-fluorophenyl)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)piperazine; (S)-2-(4-fluorophenyl)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)piperazine; (R)-2-(4-fluorophenyl)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)piperazine; 3-(4-chlorophenyl)-4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine-1- carboximidamide; (S)-3-(4-chlorophenyl)-4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine-1- carboximidamide; (R)-3-(4-chlorophenyl)-4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine-1- carboximidamide; 3-(4-((2-(4-fluorophenyl)piperazin-1-yl)methyl)pyridin-3-yl)-4- (trifluoromethoxy)phenol; (S)-3-(4-((2-(4-fluorophenyl)piperazin-1-yl)methyl)pyridin-3-yl)-4- (trifluoromethoxy)phenol; (R)-3-(4-((2-(4-fluorophenyl)piperazin-1-yl)methyl)pyridin-3-yl)-4- (trifluoromethoxy)phenol; 3-(4-fluorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; (S)-3-(4-fluorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; (R)-3-(4-fluorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; 2-(4-chlorophenyl)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)piperazine; - 111 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) (S)-2-(4-chlorophenyl)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)piperazine; (R)-2-(4-chlorophenyl)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)piperazine; 2-(4-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-4-methylpiperazine; (S)-2-(4-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-4- methylpiperazine; (R)-2-(4-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-4- methylpiperazine; 2-(4-fluorophenyl)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)-4- methylpiperazine; (S)-2-(4-fluorophenyl)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)-4- methylpiperazine; (R)-2-(4-fluorophenyl)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)-4- methylpiperazine; 5-(2-((2-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)quinoline; (S)-5-(2-((2-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)quinoline; (R)-5-(2-((2-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)quinoline; 4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-5-phenylpiperazin-2-one; (S)-4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-5-phenylpiperazin-2-one; (R)-4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-5-phenylpiperazin-2-one; 2-(4-chlorophenyl)-1-((3-phenylpyridin-4-yl)methyl)piperazine; (S)-2-(4-chlorophenyl)-1-((3-phenylpyridin-4-yl)methyl)piperazine; (R)-2-(4-chlorophenyl)-1-((3-phenylpyridin-4-yl)methyl)piperazine; 1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)-2-phenylpiperazine; (S)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)-2-phenylpiperazine; (R)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)-2-phenylpiperazine; 2'-((3-(4-chlorophenyl)morpholino)methyl)-6-(trifluoromethoxy)-[1,1'-biphenyl]-3-ol; (S)-2'-((3-(4-chlorophenyl)morpholino)methyl)-6-(trifluoromethoxy)-[1,1'-biphenyl]- 3-ol; (R)-2'-((3-(4-chlorophenyl)morpholino)methyl)-6-(trifluoromethoxy)-[1,1'-biphenyl]- 3-ol; 3-(4-chlorophenyl)-4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)morpholine; (S)-3-(4-chlorophenyl)-4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)morpholine; (R)-3-(4-chlorophenyl)-4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)morpholine; 3-(4-fluorophenyl)-4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)morpholine; - 112 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) (S)-3-(4-fluorophenyl)-4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)morpholine; (R)-3-(4-fluorophenyl)-4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)morpholine; 2'-((3-(4-chlorophenyl)morpholino)methyl)-5-(trifluoromethoxy)-[1,1'-biphenyl]-2-ol; (S)-2'-((3-(4-chlorophenyl)morpholino)methyl)-5-(trifluoromethoxy)-[1,1'-biphenyl]- 2-ol; (R)-2'-((3-(4-chlorophenyl)morpholino)methyl)-5-(trifluoromethoxy)-[1,1'-biphenyl]- 2-ol; 4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-3-phenylmorpholine; (S)-4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-3-phenylmorpholine; (R)-4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-3-phenylmorpholine; 2-(4-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperidine; (S)-2-(4-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperidine; (R)-2-(4-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperidine; 2-(4-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)pyrrolidine; (S)-2-(4-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)pyrrolidine; (R)-2-(4-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)pyrrolidine; 2-(4-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-4-(pyridin-2- yl)piperazine; (S)-2-(4-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-4-(pyridin-2- yl)piperazine; and (R)-2-(4-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-4-(pyridin-2- yl)piperazine. Embodiment 14 provides a compound of Formula (II), or a salt, solvate, stereoisomer, or isotopologue thereof: , wherein: X2 is selected from the group consisting of S, O, and N(R11); X3 is selected from the group consisting of C(R7c) and N; Y1 and Y2 are each independently selected from the group consisting of N and C(R7g); L3 is -[C(R7e)(R7f)]1-3- or a bond; - 113 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) L4 is selected from the group consisting of a bond, -C(=O)-, and -C(R7h)(R7i)-; each occurrence of R7a, R7b, R7c, R7d, R7e, R7f, R7g, R7h, and R7i is each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 heteroalkyl, halogen, CN, NO2, ORD, N(RD)(RE), C(=O)ORD, and C(=O)N(RD)(RE); R8 is optionally substituted C6-C10 aryl; R9 is selected from the group consisting of optionally substituted C6-C10 aryl and optionally substituted C2-C8 heteroaryl; R10a and R10b are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 heteroalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C6-C10 aryl, and optionally substituted C2-C8 heteroaryl, wherein R10a and R10b can combine with the atoms to which they are bound to form an optionally substituted C3-C8 heterocycloalkyl; R11 is selected from the group consisting of H and optionally substituted C1-C6 alkyl; each occurrence of RD and RE, if present, is selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 heteroalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C6-C10 aryl, and optionally substituted C2-C8 heteroaryl. Embodiment 15 provides the compound of Embodiment 14, wherein at least one of the following applies: (a) at least one of R7a, R7b, R7c, and R7d is H; (b) at least two of R7a, R7b, R7c, and R7d are H; (c) at least three of R7a, R7b, R7c, and R7d are H; and (d) each of R7a, R7b, R7c, and R7d are H. Embodiment 16 provides the compound of Embodiment 14 or 15, wherein each occurrence of R7e and R7f is independently selected from the group consisting of H, CH3, . the compound of any one of Embodiments 14-16, wherein R8 is phenyl optionally substituted with at least one halogen. Embodiment 18 provides the compound of any one of Embodiments 14-17, wherein R8 is selected from the group consisting of phenyl, 4-chlorophenyl, and 4-fluorophenyl. Embodiment 19 provides the compound of any one of Embodiments 14-18, wherein - 114 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) L3 is selected from the group consisting of a bond, -(CH2)-, -(CHCH3)-, - . of any one of Embodiments 14-19, wherein substituted phenyl, optionally substituted naphthyl, and optionally substituted indolyl. Embodiment 21 provides the compound of Embodiment 20, wherein the phenyl, naphthyl, or indolyl is optionally substituted with at least one C1-C6 haloalkyl, optionally wherein the haloalkyl is CF3. Embodiment 22 provides the compound of any one of Embodiments 14-21, wherein , , . R10a and R10b are each independently selected from the group consisting of H, C1-C6 alkyl, and optionally substituted C3-C6 cycloalkyl, optionally wherein R10a and R10b are each - 115 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) independently selected from the group consisting of H, CH3, . Embodiment 25 provides the compound of any one of 24, wherein one of the following applies: ; ; Embodiment 26 provides the compound of any one of Embodiments 14-25, wherein the compound is selected from the group consisting of: 2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(cyclopropyl(phenyl)methyl)-N-methyl-1H- benzo[d]imidazole-5-carboxamide; (R)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(cyclopropyl(phenyl)methyl)-N-methyl-1H- benzo[d]imidazole-5-carboxamide; (S)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(cyclopropyl(phenyl)methyl)-N-methyl-1H- benzo[d]imidazole-5-carboxamide; 1-benzyl-N-methyl-2-(4-phenylthiazol-2-yl)-1H-benzo[d]imidazole-5-carboxamide; 2-(4-(4-chlorophenyl)thiazol-2-yl)-N-methyl-1-(1-(4-(trifluoromethyl)phenyl)ethyl)- 1H-benzo[d]imidazole-5-carboxamide; (R)-2-(4-(4-chlorophenyl)thiazol-2-yl)-N-methyl-1-(1-(4- (trifluoromethyl)phenyl)ethyl)-1H-benzo[d]imidazole-5-carboxamide; (S)-2-(4-(4-chlorophenyl)thiazol-2-yl)-N-methyl-1-(1-(4- (trifluoromethyl)phenyl)ethyl)-1H-benzo[d]imidazole-5-carboxamide; 2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-methoxy-1-phenylethyl)-N-methyl-1H- benzo[d]imidazole-5-carboxamide; (R)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-methoxy-1-phenylethyl)-N-methyl-1H- benzo[d]imidazole-5-carboxamide; (S)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-methoxy-1-phenylethyl)-N-methyl-1H- benzo[d]imidazole-5-carboxamide; - 116 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) N-methyl-2-(4-phenylthiazol-2-yl)-1H-benzo[d]imidazole-5-carboxamide; 2-(4-(4-chlorophenyl)thiazol-2-yl)-N-methyl-1H-benzo[d]imidazole-5-carboxamide; 1-benzyl-2-(4-(4-chlorophenyl)thiazol-2-yl)-N-methyl-1H-benzo[d]imidazole-5- carboxamide; 1-((1H-indol-4-yl)methyl)-2-(4-(4-chlorophenyl)thiazol-2-yl)-N-methyl-1H- benzo[d]imidazole-5-carboxamide; 2-(4-(4-chlorophenyl)thiazol-2-yl)-N-methyl-1-(1-(naphthalen-2-yl)ethyl)-1H- benzo[d]imidazole-5-carboxamide; (R)-2-(4-(4-chlorophenyl)thiazol-2-yl)-N-methyl-1-(1-(naphthalen-2-yl)ethyl)-1H- benzo[d]imidazole-5-carboxamide; (S)-2-(4-(4-chlorophenyl)thiazol-2-yl)-N-methyl-1-(1-(naphthalen-2-yl)ethyl)-1H- benzo[d]imidazole-5-carboxamide; 2-(4-(4-chlorophenyl)thiazol-2-yl)-N-methyl-1-(1-(4-(trifluoromethyl)phenyl)ethyl)- 1H-benzo[d]imidazole-5-carboxamide; (R)-2-(4-(4-chlorophenyl)thiazol-2-yl)-N-methyl-1-(1-(4- (trifluoromethyl)phenyl)ethyl)-1H-benzo[d]imidazole-5-carboxamide; (S)-2-(4-(4-chlorophenyl)thiazol-2-yl)-N-methyl-1-(1-(4- (trifluoromethyl)phenyl)ethyl)-1H-benzo[d]imidazole-5-carboxamide; 2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-methoxy-1-phenylethyl)-N-methyl-1H- benzo[d]imidazole-5-carboxamide; (R)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-methoxy-1-phenylethyl)-N-methyl-1H- benzo[d]imidazole-5-carboxamide; (S)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-methoxy-1-phenylethyl)-N-methyl-1H- benzo[d]imidazole-5-carboxamide; 1-(cyclopropyl(phenyl)methyl)-2-(4-(4-fluorophenyl)thiazol-2-yl)-N-methyl-1H- benzo[d]imidazole-5-carboxamide; (R)-1-(cyclopropyl(phenyl)methyl)-2-(4-(4-fluorophenyl)thiazol-2-yl)-N-methyl-1H- benzo[d]imidazole-5-carboxamide; (S)-1-(cyclopropyl(phenyl)methyl)-2-(4-(4-fluorophenyl)thiazol-2-yl)-N-methyl-1H- benzo[d]imidazole-5-carboxamide; 2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(cyclopropyl(phenyl)methyl)-N,N-dimethyl-1H- benzo[d]imidazole-5-carboxamide; (R)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(cyclopropyl(phenyl)methyl)-N,N-dimethyl- 1H-benzo[d]imidazole-5-carboxamide; - 117 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) (S)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(cyclopropyl(phenyl)methyl)-N,N-dimethyl- 1H-benzo[d]imidazole-5-carboxamide; 2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(cyclopropyl(phenyl)methyl)-1H- benzo[d]imidazole-5-carboxamide; (R)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(cyclopropyl(phenyl)methyl)-1H- benzo[d]imidazole-5-carboxamide; (S)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(cyclopropyl(phenyl)methyl)-1H- benzo[d]imidazole-5-carboxamide; 2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-methoxy-1-phenylethyl)-1H- benzo[d]imidazole-5-carboxamide; (R)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-methoxy-1-phenylethyl)-1H- benzo[d]imidazole-5-carboxamide; (S)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-methoxy-1-phenylethyl)-1H- benzo[d]imidazole-5-carboxamide; 2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-methoxy-1-phenylethyl)-N,N-dimethyl-1H- benzo[d]imidazole-5-carboxamide; (R)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-methoxy-1-phenylethyl)-N,N-dimethyl- 1H-benzo[d]imidazole-5-carboxamide; (S)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-methoxy-1-phenylethyl)-N,N-dimethyl- 1H-benzo[d]imidazole-5-carboxamide; 2-(4-(4-chlorophenyl)thiazol-2-yl)-3-(cyclopropyl(phenyl)methyl)-3H-imidazo[4,5- b]pyridine-6-carboxamide; (R)-2-(4-(4-chlorophenyl)thiazol-2-yl)-3-(cyclopropyl(phenyl)methyl)-3H- imidazo[4,5-b]pyridine-6-carboxamide; and (S)-2-(4-(4-chlorophenyl)thiazol-2-yl)-3-(cyclopropyl(phenyl)methyl)-3H- imidazo[4,5-b]pyridine-6-carboxamide. Embodiment 27 provides a pharmaceutical composition comprising at least one compound of any one of Embodiments 1-26 and a pharmaceutically acceptable carrier or excipient. Embodiment 28 provides the pharmaceutical composition of Embodiment 27, further comprising at least one additional agent suitable for treating, preventing, and/or ameliorating a bacterial infection. Embodiment 29 provides the pharmaceutical composition of Embodiment 28, wherein the at least one additional agent suitable for treating, preventing, and/or ameliorating a - 118 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) bacterial infection is selected from the group consisting of a polymyxin, aminoglycoside, β- lactam (e.g., penicillin, cephalosporin, or carbapenem), monobactam, fluoroquinolone, sulfonamide, tetracycline, and macrolide. Embodiment 30 provides the pharmaceutical composition of Embodiment 28 or 29, wherein the additional agent suitable for treating, preventing, and/or ameliorating a bacterial infection is at least one selected from the group consisting of colistin (polymyxin E), polymyxin B, amikacin, ampicillin, amoxicillin aminoglycoside, azithromycin, aztreonam, carbapenem, cefepime, cefiderocol, cefotaxime, ceftriaxone, ceftaroline, ceftazidime, ceftobiprole, ceftolozane, ciprofloxacin, clindamycin, dalbavancin, daptomycin, doxycycline, ertapenem, fluoroquinolone, gentamicin, imipenem, levofloxacin, linezolid, meropenem, minocycline, mupirocin, oritavancin, piperacillin, streptogramin, sulbactam, tedizolid, telavancin, tigecycline, ticarcillin, tobramycin, trimethoprim/sulfamethoxazole, and vancomycin. Embodiment 31 provides a method of treating, preventing, and/or ameliorating a bacterial infection in a subject, the method comprising administering to the subject: (a) at least one compound of any one of Embodiments 1-26 or the pharmaceutical composition of any one of Embodiments 27-30; and (b) at least one polymyxin antibiotic, or an analogue or derivative thereof. Embodiment 32 provides a method of sensitizing a bacterial colony to at least one antibiotic polypeptide, the method comprising contacting the bacterial colony with at least one compound of any one of Embodiments 1-26, or the pharmaceutical composition of any one of Embodiments 27-30. Embodiment 33 provides the method of Embodiment 31 or 32, wherein the antibiotic peptide is at least one selected from the group consisting of a polymyxin antibiotic and a defensin, optionally wherein the polymyxin antibiotic is selected from the group consisting of colistin (polymyxin E) and polymyxin B. Embodiment 34 provides the method of any one of Embodiments 31-33, wherein the bacterial infection or bacterial colony comprises a bacterial species selected from the group consisting of: Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus lugdenensis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus saprophyticus, Staphylococcus simulans, Staphylococcus warnerii, Staphylococcus capitis, Staphylococcus caprae, Staphylococcus pettenkoferi, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus pneumoniae, Group C streptococci, Streptococcus constellatus, Enterococcus faecalis, Enterococcus faecium, Corynebacterium jeikeium, Lactobacillus - 119 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) acidophilus, Listeria monocytogenes, Escherichia coli, Klebsiella pneumoniae, Klebsiella aerogenes, Klebsiella oxytoca, Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter nosocomialis, Acinetobacter pittii, Acinetobacter haemolyticus, Acetinobacter johnsonii, Acinetobacter lwoffi, Acinetobacter radioresistens, Acinetobacter ursingii, Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas putida, Enterobacter cloacae, Enterobacter aerogenes, Stenotrophomonas maltophilia, Citrobacter freundii, Citrobacter koseri, Citrobacter sedlakii, Citrobacter braakii, Morganella morganii, Providencia rettgeri, Providencia stuartii, Salmonella typhimurium, Shigella dysenteriae, Moraxella catarrhalis, Neisseria gonorrhoeae, Propionibacterium acnes, Clostridioides difficile, Clostridioides perfringens, Bacteroides fragilis, Prevotella bivia, Eggerthella lenta, Peptostreptococcus anaerobius, and any combination thereof. Embodiment 35 provides the method of any one of Embodiments 31-34, wherein the method further comprises administering at least one additional antibiotic. Embodiment 36 provides the method of Embodiment 35, wherein the additional antibiotic is at least one selected from the group consisting of a aminoglycoside, β-lactam (e.g., penicillin, cephalosporin, or carbapenem), monobactam, fluoroquinolone, sulfonamide, tetracycline, and macrolide. Embodiment 37 provides the method of Embodiment 35 or 36, wherein the additional antibiotic is at least one selected from the group consisting of amikacin, aminoglycoside, azithromycin, aztreonam, carbapenem, cefepime, ceftriaxone, ceftaroline, ceftazidime, ceftobiprole, ceftolozane, ciprofloxacin, clindamycin, dalbavancin, daptomycin, doxycycline, ertapenem, fluoroquinolone, gentamicin, imipenem, levofloxacin, linezolid, meropenem, minocycline, mupirocin, oritavancin, piperacillin, streptogramin, tedizolid, telavancin, tigecycline, ticarcillin, tobramycin, trimethoprim/sulfamethoxazole, and vancomycin, or a combination thereof. Embodiment 38 provides the method of any one of Embodiments 31 and 33-37, wherein the bacterial infection is a persistent or antibiotic resistant bacterial infection. Embodiment 39 provides the method of any one of Embodiments 31-38, wherein formation of a bacterial biofilm is at least partially prevented or inhibited. Embodiment 40 provides the method of any one of Embodiments 31 and 33-39, wherein the infection occurs on a prosthesis or an implant. Embodiment 41 provides the method of Embodiment 40, wherein the prosthesis selected from the group consisting of a knee prosthesis, a hip prosthesis, elbow prosthesis, ankle prosthesis, shoulder prosthesis, and spine prosthesis. - 120 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) Embodiment 42 provides the method of any one of Embodiments 31 and 33-41, wherein the subject is a mammal. Embodiment 43 provides the method of any one of Embodiments 31 and 33-42, wherein the subject is a human. The terms and expressions employed herein are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the embodiments of the present application. Thus, it should be understood that although the present application describes specific embodiments and optional features, modification and variation of the compositions, methods, and concepts herein disclosed may be resorted to by those of ordinary skill in the art, and that such modifications and variations are considered to be within the scope of embodiments of the present application. - 121 - 55708207.3

Claims

Attorney Docket No.046641-7064WO1(00175) CLAIMS What is claimed is: 1. A compound of Formula (I), or a salt, solvate, stereoisomer, or isotopologue thereof: , wherein: R1 is selected from the substituted C6-C10 aryl and optionally substituted C2-C8 heteroaryl; R2a, R2b, R2c, R2d, R2e, R2f, R2g, R2h, R2i, R2j, R2k, and R2l, if present, are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 heteroalkyl, halogen, CN, NO2, ORA, N(RA)(RB), C(=O)ORA, and C(=O)N(RA)(RB), wherein two geminal substituents selected from R2a, R2b, R2c, R2d, R2e, R2f, R2g, R2h, R2i, R2j, R2k, and R2l can combine with the carbon atom to which they are bound to form C(=O); and wherein one of R2b and R2c is R3; R3 is optionally substituted C6-C10 aryl; L1 is selected from the group consisting of a bond and -C(R2g)(R2h)-; L2 is selected from the group consisting of a bond and -C(R2i)(R2j)-; X1 is selected from the group consisting of -N(R4)-, -O-, and -C(R2k)(R2l)-; R4, if present, is selected from the group consisting of H, optionally substituted C1-C6 alkyl, C(=O)RA, C(=O)ORA, C(=O)N(RA)(RB), C(=NRA)N(RB)(RC), optionally substituted C6-C10 aryl, and optionally substituted C2-C8 heteroaryl; and each occurrence of RA, RB, and RC, if present, is selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 heteroalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C6-C10 aryl, and optionally substituted C2-C8 heteroaryl. 2. The compound of claim 1, wherein the compound of Formula (I) is selected from the group consisting of: - 122 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) , . 3. The (I) is selected from the group consisting of: R4 N 2), 2). 4. The compound of any one of claims 1-3, wherein R1 is selected from the group consisting of: , wherein R5a, R5b, R5c, R5d, selected from the group consisting of H, halogen, CN, NO2, ORA, N(RA)(RB), optionally substituted C1-C6 alkyl, optionally substituted C6-C10 aryl, and optionally substituted C2-C10 heteroaryl. - 123 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) 5. The compound of claim 4, wherein at least one of R5a, R5b, R5c, R5d, and R5e is phenyl, optionally wherein the phenyl is substituted with at least one selected from the group consisting of OH, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkyl, and C1-C6 haloalkyl. 6. The compound of claim 4 or 5, wherein R5a, R5b, R5c, R5d, and R5e, if present, are each independently selected from the group consisting of H, CH3, , . each of the following apply: (a) R5b, R5c, and R5d, if present, are each independently H or CH3; (b) one of R5a and R5e is selected from the group consisting of , (c) 8. The compound of any one of claims 1-7, wherein R1 is selected from the group 9. The compound of any one of claims 1-8, wherein R3 is: - 124 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) , wherein R6a, R6b, R6c, R6d, and R6e are selected from the group consisting of H, optionally substituted C1-C6 substituted C2-C6 haloalkyl, optionally substituted C6-C10 aryl, optionally substituted C2-C10 heteroaryl, halogen, CN, NO2, ORA, N(RA)(RB), C(=O)N(RA)(RB), C(=O)RA, C(=O)ORA, and S(=O)2N(RA)(RB). 10. The compound of claim of 9, wherein R6a, R6b, R6c, R6d, and R6e are each independently selected from the group consisting of H, F, and Cl, optionally wherein one of R6a, R6b, R6c, R6d, and R6e is F or Cl. 11. The compound of any one of claims 1-10, wherein R3 is selected from the group . 12. The compound of any one of claims 1-11, wherein R4 is selected from the group . 13. any one from the group consisting of: 4-(3-(4-chlorophenyl)-4-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)piperazine-1- carbonyl)-N-methylbenzamide; (S)-4-(3-(4-chlorophenyl)-4-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)piperazine-1- carbonyl)-N-methylbenzamide; (R)-4-(3-(4-chlorophenyl)-4-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)piperazine- 1-carbonyl)-N-methylbenzamide; 2-(4-fluorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-4-methylpiperazine; (S)-2-(4-fluorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-4- - 125 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) methylpiperazine; (R)-2-(4-fluorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-4- methylpiperazine; 2-(4-chlorophenyl)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)piperazine; (S)-2-(4-chlorophenyl)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)piperazine; (R)-2-(4-chlorophenyl)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)piperazine; 3-(4-((2-(4-chlorophenyl)piperazin-1-yl)methyl)pyridin-3-yl)-4- (trifluoromethoxy)phenol; (S)-3-(4-((2-(4-chlorophenyl)piperazin-1-yl)methyl)pyridin-3-yl)-4- (trifluoromethoxy)phenol; (R)-3-(4-((2-(4-chlorophenyl)piperazin-1-yl)methyl)pyridin-3-yl)-4- (trifluoromethoxy)phenol; 2'-((2-(4-chlorophenyl)piperazin-1-yl)methyl)-6-(trifluoromethoxy)-[1,1'-biphenyl]-3- ol; (S)-2'-((2-(4-chlorophenyl)piperazin-1-yl)methyl)-6-(trifluoromethoxy)-[1,1'- biphenyl]-3-ol; (R)-2'-((2-(4-chlorophenyl)piperazin-1-yl)methyl)-6-(trifluoromethoxy)-[1,1'- biphenyl]-3-ol; 2'-((2-(4-fluorophenyl)piperazin-1-yl)methyl)-6-(trifluoromethoxy)-[1,1'-biphenyl]-3- ol; (S)-2'-((2-(4-fluorophenyl)piperazin-1-yl)methyl)-6-(trifluoromethoxy)-[1,1'- biphenyl]-3-ol; (R)-2'-((2-(4-fluorophenyl)piperazin-1-yl)methyl)-6-(trifluoromethoxy)-[1,1'- biphenyl]-3-ol; 2-(4-fluorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; (S)-2-(4-fluorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; (R)-2-(4-fluorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; 2-(4-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; (S)-2-(4-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; (R)-2-(4-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; 2'-((2-(3-chlorophenyl)piperazin-1-yl)methyl)-6-(trifluoromethoxy)-[1,1'-biphenyl]-3- ol; (S)-2'-((2-(3-chlorophenyl)piperazin-1-yl)methyl)-6-(trifluoromethoxy)-[1,1'- biphenyl]-3-ol; - 126 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) (R)-2'-((2-(3-chlorophenyl)piperazin-1-yl)methyl)-6-(trifluoromethoxy)-[1,1'- biphenyl]-3-ol; 2-(4-chlorophenyl)-1-((2'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)methyl)piperazine; (S)-2-(4-chlorophenyl)-1-((2'-(trifluoromethyl)-[1,1'-biphenyl]-2- yl)methyl)piperazine; (R)-2-(4-chlorophenyl)-1-((2'-(trifluoromethyl)-[1,1'-biphenyl]-2- yl)methyl)piperazine; 3-(4-((2-(4-fluorophenyl)-4-methylpiperazin-1-yl)methyl)pyridin-3-yl)-4- (trifluoromethoxy)phenol; (S)-3-(4-((2-(4-fluorophenyl)-4-methylpiperazin-1-yl)methyl)pyridin-3-yl)-4- (trifluoromethoxy)phenol; (R)-3-(4-((2-(4-fluorophenyl)-4-methylpiperazin-1-yl)methyl)pyridin-3-yl)-4- (trifluoromethoxy)phenol; 2'-((2-(4-chlorophenyl)piperazin-1-yl)methyl)-5'-methyl-6-(trifluoromethoxy)-[1,1'- biphenyl]-3-ol; (S)-2'-((2-(4-chlorophenyl)piperazin-1-yl)methyl)-5'-methyl-6-(trifluoromethoxy)- [1,1'-biphenyl]-3-ol; (R)-2'-((2-(4-chlorophenyl)piperazin-1-yl)methyl)-5'-methyl-6-(trifluoromethoxy)- [1,1'-biphenyl]-3-ol; 2'-((2-(4-fluorophenyl)-4-methylpiperazin-1-yl)methyl)-6-(trifluoromethoxy)-[1,1'- biphenyl]-3-ol; (S)-2'-((2-(4-fluorophenyl)-4-methylpiperazin-1-yl)methyl)-6-(trifluoromethoxy)- [1,1'-biphenyl]-3-ol; (R)-2'-((2-(4-fluorophenyl)-4-methylpiperazin-1-yl)methyl)-6-(trifluoromethoxy)- [1,1'-biphenyl]-3-ol; 2-(4-fluorophenyl)-4-methyl-1-((2'-(trifluoromethyl)-[1,1'-biphenyl]-2- yl)methyl)piperazine; (S)-2-(4-fluorophenyl)-4-methyl-1-((2'-(trifluoromethyl)-[1,1'-biphenyl]-2- yl)methyl)piperazine; (R)-2-(4-fluorophenyl)-4-methyl-1-((2'-(trifluoromethyl)-[1,1'-biphenyl]-2- yl)methyl)piperazine; 2-(3-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; (S)-2-(3-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; (R)-2-(3-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; - 127 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) 2-(2-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; (S)-2-(2-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; (R)-2-(2-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; 2'-((2-(4-fluorophenyl)piperazin-1-yl)methyl)-6-(trifluoromethoxy)-[1,1'-biphenyl]-3- ol; (S)-2'-((2-(4-fluorophenyl)piperazin-1-yl)methyl)-6-(trifluoromethoxy)-[1,1'- biphenyl]-3-ol; (R)-2'-((2-(4-fluorophenyl)piperazin-1-yl)methyl)-6-(trifluoromethoxy)-[1,1'- biphenyl]-3-ol; 2-(4-fluorophenyl)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)piperazine; (S)-2-(4-fluorophenyl)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)piperazine; (R)-2-(4-fluorophenyl)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)piperazine; 3-(4-chlorophenyl)-4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine-1- carboximidamide; (S)-3-(4-chlorophenyl)-4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine-1- carboximidamide; (R)-3-(4-chlorophenyl)-4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine-1- carboximidamide; 3-(4-((2-(4-fluorophenyl)piperazin-1-yl)methyl)pyridin-3-yl)-4- (trifluoromethoxy)phenol; (S)-3-(4-((2-(4-fluorophenyl)piperazin-1-yl)methyl)pyridin-3-yl)-4- (trifluoromethoxy)phenol; (R)-3-(4-((2-(4-fluorophenyl)piperazin-1-yl)methyl)pyridin-3-yl)-4- (trifluoromethoxy)phenol; 3-(4-fluorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; (S)-3-(4-fluorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; (R)-3-(4-fluorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperazine; 2-(4-chlorophenyl)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)piperazine; (S)-2-(4-chlorophenyl)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)piperazine; (R)-2-(4-chlorophenyl)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)piperazine; 2-(4-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-4-methylpiperazine; (S)-2-(4-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-4- methylpiperazine; (R)-2-(4-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-4- - 128 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) methylpiperazine; 2-(4-fluorophenyl)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)-4- methylpiperazine; (S)-2-(4-fluorophenyl)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)-4- methylpiperazine; (R)-2-(4-fluorophenyl)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)-4- methylpiperazine; 5-(2-((2-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)quinoline; (S)-5-(2-((2-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)quinoline; (R)-5-(2-((2-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)quinoline; 4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-5-phenylpiperazin-2-one; (S)-4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-5-phenylpiperazin-2-one; (R)-4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-5-phenylpiperazin-2-one; 2-(4-chlorophenyl)-1-((3-phenylpyridin-4-yl)methyl)piperazine; (S)-2-(4-chlorophenyl)-1-((3-phenylpyridin-4-yl)methyl)piperazine; (R)-2-(4-chlorophenyl)-1-((3-phenylpyridin-4-yl)methyl)piperazine; 1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)-2-phenylpiperazine; (S)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)-2-phenylpiperazine; (R)-1-((3-(2-isopropylphenyl)pyridin-4-yl)methyl)-2-phenylpiperazine; 2'-((3-(4-chlorophenyl)morpholino)methyl)-6-(trifluoromethoxy)-[1,1'-biphenyl]-3-ol; (S)-2'-((3-(4-chlorophenyl)morpholino)methyl)-6-(trifluoromethoxy)-[1,1'-biphenyl]- 3-ol; (R)-2'-((3-(4-chlorophenyl)morpholino)methyl)-6-(trifluoromethoxy)-[1,1'-biphenyl]- 3-ol; 3-(4-chlorophenyl)-4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)morpholine; (S)-3-(4-chlorophenyl)-4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)morpholine; (R)-3-(4-chlorophenyl)-4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)morpholine; 3-(4-fluorophenyl)-4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)morpholine; (S)-3-(4-fluorophenyl)-4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)morpholine; (R)-3-(4-fluorophenyl)-4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)morpholine; 2'-((3-(4-chlorophenyl)morpholino)methyl)-5-(trifluoromethoxy)-[1,1'-biphenyl]-2-ol; (S)-2'-((3-(4-chlorophenyl)morpholino)methyl)-5-(trifluoromethoxy)-[1,1'-biphenyl]- 2-ol; (R)-2'-((3-(4-chlorophenyl)morpholino)methyl)-5-(trifluoromethoxy)-[1,1'-biphenyl]- - 129 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) 2-ol; 4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-3-phenylmorpholine; (S)-4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-3-phenylmorpholine; (R)-4-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-3-phenylmorpholine; 2-(4-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperidine; (S)-2-(4-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperidine; (R)-2-(4-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)piperidine; 2-(4-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)pyrrolidine; (S)-2-(4-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)pyrrolidine; (R)-2-(4-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)pyrrolidine; 2-(4-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-4-(pyridin-2- yl)piperazine; (S)-2-(4-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-4-(pyridin-2- yl)piperazine; and (R)-2-(4-chlorophenyl)-1-((2'-isopropyl-[1,1'-biphenyl]-2-yl)methyl)-4-(pyridin-2- yl)piperazine. 14. A compound of Formula (II), or a salt, solvate, stereoisomer, or isotopologue thereof: , wherein: X2 is selected from the group consisting of S, O, and N(R11); X3 is selected from the group consisting of C(R7c) and N; Y1 and Y2 are each independently selected from the group consisting of N and C(R7g); L3 is -[C(R7e)(R7f)]1-3- or a bond; L4 is selected from the group consisting of a bond, -C(=O)-, and -C(R7h)(R7i)-; each occurrence of R7a, R7b, R7c, R7d, R7e, R7f, R7g, R7h, and R7i is each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 heteroalkyl, halogen, CN, NO2, ORD, N(RD)(RE), C(=O)ORD, and C(=O)N(RD)(RE); R8 is optionally substituted C6-C10 aryl; - 130 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) R9 is selected from the group consisting of H, optionally substituted C6-C10 aryl, and optionally substituted C2-C8 heteroaryl; R10a and R10b are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 heteroalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C6-C10 aryl, and optionally substituted C2-C8 heteroaryl, wherein R10a and R10b can combine with the atoms to which they are bound to form an optionally substituted C3-C8 heterocycloalkyl; R11 is selected from the group consisting of H and optionally substituted C1-C6 alkyl; each occurrence of RD and RE, if present, is selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 heteroalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C6-C10 aryl, and optionally substituted C2-C8 heteroaryl. 15. The compound of claim 14, wherein at least one of the following applies: (a) at least one of R7a, R7b, R7c, and R7d is H; (b) at least two of R7a, R7b, R7c, and R7d are H; (c) at least three of R7a, R7b, R7c, and R7d are H; and (d) each of R7a, R7b, R7c, and R7d are H. 16. The compound of claim 14 or 15, wherein each occurrence of R7e and R7f is independently selected from the group consisting of H, CH3, CH2OCH3, , and . 17. The compound of any one of claims 14-16, wherein R8 is phenyl optionally substituted with at least one halogen. 18. The compound of any one of claims 14-17, wherein R8 is selected from the group consisting of phenyl, 4-chlorophenyl, and 4-fluorophenyl. 19. The compound of any one of claims 14-18, wherein L3 is selected from the group - 131 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) consisting of a bond, . 20. The consisting of H, optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted indolyl. 21. The compound of claim 20, wherein the phenyl, naphthyl, or indolyl is optionally substituted with at least one C1-C6 haloalkyl, optionally wherein the haloalkyl is CF3. 22. The compound of any one of claims 14-21, wherein R9 is selected from the group . 23. The compound of any one of claims 14-22, wherein the combination of L3-R9 is selected from the group consisting of , , , 24. The compound of any one of claims 14-23, wherein R10a and R10b are each independently selected from the group consisting of H, C1-C6 alkyl, and optionally substituted C3-C6 cycloalkyl, optionally wherein R10a and R10b are each independently - 132 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) selected from the group consisting of H, CH3, . 25. The compound of any one of claims 14-24, wherein one of the following applies: ; ; 26. The compound of any one of claims 14-25, wherein the compound is selected from the group consisting of: 2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(cyclopropyl(phenyl)methyl)-N-methyl-1H- benzo[d]imidazole-5-carboxamide; (R)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(cyclopropyl(phenyl)methyl)-N-methyl-1H- benzo[d]imidazole-5-carboxamide; (S)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(cyclopropyl(phenyl)methyl)-N-methyl-1H- benzo[d]imidazole-5-carboxamide; 1-benzyl-N-methyl-2-(4-phenylthiazol-2-yl)-1H-benzo[d]imidazole-5-carboxamide; 2-(4-(4-chlorophenyl)thiazol-2-yl)-N-methyl-1-(1-(4-(trifluoromethyl)phenyl)ethyl)- 1H-benzo[d]imidazole-5-carboxamide; (R)-2-(4-(4-chlorophenyl)thiazol-2-yl)-N-methyl-1-(1-(4- (trifluoromethyl)phenyl)ethyl)-1H-benzo[d]imidazole-5-carboxamide; (S)-2-(4-(4-chlorophenyl)thiazol-2-yl)-N-methyl-1-(1-(4- (trifluoromethyl)phenyl)ethyl)-1H-benzo[d]imidazole-5-carboxamide; 2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-methoxy-1-phenylethyl)-N-methyl-1H- benzo[d]imidazole-5-carboxamide; (R)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-methoxy-1-phenylethyl)-N-methyl-1H- benzo[d]imidazole-5-carboxamide; - 133 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) (S)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-methoxy-1-phenylethyl)-N-methyl-1H- benzo[d]imidazole-5-carboxamide; N-methyl-2-(4-phenylthiazol-2-yl)-1H-benzo[d]imidazole-5-carboxamide; 2-(4-(4-chlorophenyl)thiazol-2-yl)-N-methyl-1H-benzo[d]imidazole-5-carboxamide; 1-benzyl-2-(4-(4-chlorophenyl)thiazol-2-yl)-N-methyl-1H-benzo[d]imidazole-5- carboxamide; 1-((1H-indol-4-yl)methyl)-2-(4-(4-chlorophenyl)thiazol-2-yl)-N-methyl-1H- benzo[d]imidazole-5-carboxamide; 2-(4-(4-chlorophenyl)thiazol-2-yl)-N-methyl-1-(1-(naphthalen-2-yl)ethyl)-1H- benzo[d]imidazole-5-carboxamide; (R)-2-(4-(4-chlorophenyl)thiazol-2-yl)-N-methyl-1-(1-(naphthalen-2-yl)ethyl)-1H- benzo[d]imidazole-5-carboxamide; (S)-2-(4-(4-chlorophenyl)thiazol-2-yl)-N-methyl-1-(1-(naphthalen-2-yl)ethyl)-1H- benzo[d]imidazole-5-carboxamide; 2-(4-(4-chlorophenyl)thiazol-2-yl)-N-methyl-1-(1-(4-(trifluoromethyl)phenyl)ethyl)- 1H-benzo[d]imidazole-5-carboxamide; (R)-2-(4-(4-chlorophenyl)thiazol-2-yl)-N-methyl-1-(1-(4- (trifluoromethyl)phenyl)ethyl)-1H-benzo[d]imidazole-5-carboxamide; (S)-2-(4-(4-chlorophenyl)thiazol-2-yl)-N-methyl-1-(1-(4- (trifluoromethyl)phenyl)ethyl)-1H-benzo[d]imidazole-5-carboxamide; 2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-methoxy-1-phenylethyl)-N-methyl-1H- benzo[d]imidazole-5-carboxamide; (R)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-methoxy-1-phenylethyl)-N-methyl-1H- benzo[d]imidazole-5-carboxamide; (S)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-methoxy-1-phenylethyl)-N-methyl-1H- benzo[d]imidazole-5-carboxamide; 1-(cyclopropyl(phenyl)methyl)-2-(4-(4-fluorophenyl)thiazol-2-yl)-N-methyl-1H- benzo[d]imidazole-5-carboxamide; (R)-1-(cyclopropyl(phenyl)methyl)-2-(4-(4-fluorophenyl)thiazol-2-yl)-N-methyl-1H- benzo[d]imidazole-5-carboxamide; (S)-1-(cyclopropyl(phenyl)methyl)-2-(4-(4-fluorophenyl)thiazol-2-yl)-N-methyl-1H- benzo[d]imidazole-5-carboxamide; 2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(cyclopropyl(phenyl)methyl)-N,N-dimethyl-1H- benzo[d]imidazole-5-carboxamide; - 134 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) (R)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(cyclopropyl(phenyl)methyl)-N,N-dimethyl- 1H-benzo[d]imidazole-5-carboxamide; (S)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(cyclopropyl(phenyl)methyl)-N,N-dimethyl- 1H-benzo[d]imidazole-5-carboxamide; 2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(cyclopropyl(phenyl)methyl)-1H- benzo[d]imidazole-5-carboxamide; (R)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(cyclopropyl(phenyl)methyl)-1H- benzo[d]imidazole-5-carboxamide; (S)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(cyclopropyl(phenyl)methyl)-1H- benzo[d]imidazole-5-carboxamide; 2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-methoxy-1-phenylethyl)-1H- benzo[d]imidazole-5-carboxamide; (R)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-methoxy-1-phenylethyl)-1H- benzo[d]imidazole-5-carboxamide; (S)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-methoxy-1-phenylethyl)-1H- benzo[d]imidazole-5-carboxamide; 2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-methoxy-1-phenylethyl)-N,N-dimethyl-1H- benzo[d]imidazole-5-carboxamide; (R)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-methoxy-1-phenylethyl)-N,N-dimethyl- 1H-benzo[d]imidazole-5-carboxamide; (S)-2-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-methoxy-1-phenylethyl)-N,N-dimethyl- 1H-benzo[d]imidazole-5-carboxamide; 2-(4-(4-chlorophenyl)thiazol-2-yl)-3-(cyclopropyl(phenyl)methyl)-3H-imidazo[4,5- b]pyridine-6-carboxamide; (R)-2-(4-(4-chlorophenyl)thiazol-2-yl)-3-(cyclopropyl(phenyl)methyl)-3H- imidazo[4,5-b]pyridine-6-carboxamide; and (S)-2-(4-(4-chlorophenyl)thiazol-2-yl)-3-(cyclopropyl(phenyl)methyl)-3H- imidazo[4,5-b]pyridine-6-carboxamide. 27. A pharmaceutical composition comprising at least one compound of any one of claims 1-26 and a pharmaceutically acceptable carrier or excipient. 28. The pharmaceutical composition of claim 27, further comprising at least one additional agent suitable for treating, preventing, and/or ameliorating a bacterial infection. - 135 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) 29. The pharmaceutical composition of claim 28, wherein the at least one additional agent suitable for treating, preventing, and/or ameliorating a bacterial infection is selected from the group consisting of a polymyxin, aminoglycoside, β-lactam (e.g., penicillin, cephalosporin, or carbapenem), monobactam, fluoroquinolone, sulfonamide, tetracycline, and macrolide. 30. The pharmaceutical composition of claim 28 or 29, wherein the additional agent suitable for treating, preventing, and/or ameliorating a bacterial infection is at least one selected from the group consisting of colistin (polymyxin E), polymyxin B, amikacin, ampicillin, amoxicillin aminoglycoside, azithromycin, aztreonam, carbapenem, cefepime, cefiderocol, cefotaxime, ceftriaxone, ceftaroline, ceftazidime, ceftobiprole, ceftolozane, ciprofloxacin, clindamycin, dalbavancin, daptomycin, doxycycline, ertapenem, fluoroquinolone, gentamicin, imipenem, levofloxacin, linezolid, meropenem, minocycline, mupirocin, oritavancin, piperacillin, streptogramin, sulbactam, tedizolid, telavancin, tigecycline, ticarcillin, tobramycin, trimethoprim/sulfamethoxazole, and vancomycin. 31. A method of treating, preventing, and/or ameliorating a bacterial infection in a subject, the method comprising administering to the subject: (a) at least one compound of any one of claims 1-26 or the pharmaceutical composition of any one of claims 27-30; and (b) at least one polymyxin antibiotic, or an analogue or derivative thereof. 32. A method of sensitizing a bacterial colony to at least one antibiotic polypeptide, the method comprising contacting the bacterial colony with at least one compound of any one of claims 1-26, or the pharmaceutical composition of any one of claims 27-30. 33. The method of claim 31 or 32, wherein the antibiotic peptide is at least one selected from the group consisting of a polymyxin antibiotic and a defensin, optionally wherein the polymyxin antibiotic is selected from the group consisting of colistin (polymyxin E) and polymyxin B. 34. The method of any one of claims 31-33, wherein the bacterial infection or bacterial colony comprises a bacterial species selected from the group consisting of: Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus lugdenensis, Staphylococcus - 136 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) haemolyticus, Staphylococcus hominis, Staphylococcus saprophyticus, Staphylococcus simulans, Staphylococcus warnerii, Staphylococcus capitis, Staphylococcus caprae, Staphylococcus pettenkoferi, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus pneumoniae, Group C streptococci, Streptococcus constellatus, Enterococcus faecalis, Enterococcus faecium, Corynebacterium jeikeium, Lactobacillus acidophilus, Listeria monocytogenes, Escherichia coli, Klebsiella pneumoniae, Klebsiella aerogenes, Klebsiella oxytoca, Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter nosocomialis, Acinetobacter pittii, Acinetobacter haemolyticus, Acetinobacter johnsonii, Acinetobacter lwoffi, Acinetobacter radioresistens, Acinetobacter ursingii, Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas putida, Enterobacter cloacae, Enterobacter aerogenes, Stenotrophomonas maltophilia, Citrobacter freundii, Citrobacter koseri, Citrobacter sedlakii, Citrobacter braakii, Morganella morganii, Providencia rettgeri, Providencia stuartii, Salmonella typhimurium, Shigella dysenteriae, Moraxella catarrhalis, Neisseria gonorrhoeae, Propionibacterium acnes, Clostridioides difficile, Clostridioides perfringens, Bacteroides fragilis, Prevotella bivia, Eggerthella lenta, Peptostreptococcus anaerobius, and any combination thereof. 35. The method of any one of claims 31-34, wherein the method further comprises administering at least one additional antibiotic. 36. The method of claim 35, wherein the additional antibiotic is at least one selected from the group consisting of a aminoglycoside, β-lactam (e.g., penicillin, cephalosporin, or carbapenem), monobactam, fluoroquinolone, sulfonamide, tetracycline, and macrolide. 37. The method of claim 35 or 36, wherein the additional antibiotic is at least one selected from the group consisting of amikacin, aminoglycoside, azithromycin, aztreonam, carbapenem, cefepime, ceftriaxone, ceftaroline, ceftazidime, ceftobiprole, ceftolozane, ciprofloxacin, clindamycin, dalbavancin, daptomycin, doxycycline, ertapenem, fluoroquinolone, gentamicin, imipenem, levofloxacin, linezolid, meropenem, minocycline, mupirocin, oritavancin, piperacillin, streptogramin, tedizolid, telavancin, tigecycline, ticarcillin, tobramycin, trimethoprim/sulfamethoxazole, and vancomycin, or a combination thereof. 38. The method of any one of claims 31 and 33-37, wherein the bacterial infection is a - 137 - 55708207.3 Attorney Docket No.046641-7064WO1(00175) persistent or antibiotic resistant bacterial infection. 39. The method of any one of claims 31-38, wherein formation of a bacterial biofilm is at least partially prevented or inhibited. 40. The method of any one of claims 31 and 33-39, wherein the infection occurs on a prosthesis or an implant. 41. The method of claim 40, wherein the prosthesis selected from the group consisting of a knee prosthesis, a hip prosthesis, elbow prosthesis, ankle prosthesis, shoulder prosthesis, and spine prosthesis. 42. The method of any one of claims 31 and 33-41, wherein the subject is a mammal. 43. The method of any one of claims 31 and 33-42, wherein the subject is a human. - 138 - 55708207.3
PCT/US2025/033970 2024-06-17 2025-06-17 Inhibitors of mobilized colistin resistance enzyme (mcr-1) and methods of use thereof Pending WO2025264672A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202463660713P 2024-06-17 2024-06-17
US63/660,713 2024-06-17

Publications (1)

Publication Number Publication Date
WO2025264672A1 true WO2025264672A1 (en) 2025-12-26

Family

ID=98213916

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2025/033970 Pending WO2025264672A1 (en) 2024-06-17 2025-06-17 Inhibitors of mobilized colistin resistance enzyme (mcr-1) and methods of use thereof

Country Status (1)

Country Link
WO (1) WO2025264672A1 (en)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3965114A (en) * 1973-09-20 1976-06-22 Akzona Incorporated Imidazolidine derivatives
WO2005014555A1 (en) * 2003-07-21 2005-02-17 Aventis Pharmaceuticals Inc. 4,5-dihydro-imidazole as p2x7 ion channel blockers
WO2007066784A2 (en) * 2005-12-05 2007-06-14 Otsuka Pharmaceutical Co., Ltd. Diarylether derivatives as antitumor agents

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3965114A (en) * 1973-09-20 1976-06-22 Akzona Incorporated Imidazolidine derivatives
WO2005014555A1 (en) * 2003-07-21 2005-02-17 Aventis Pharmaceuticals Inc. 4,5-dihydro-imidazole as p2x7 ion channel blockers
WO2007066784A2 (en) * 2005-12-05 2007-06-14 Otsuka Pharmaceutical Co., Ltd. Diarylether derivatives as antitumor agents

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE PUBCHEM COMPOUND 5 December 2007 (2007-12-05), XP093386351, Database accession no. 21527900 *
MUCCIOLI GIULIO G., FAZIO NICOLA, SCRIBA GERHARD K. E., POPPITZ WOLFGANG, CANNATA FABIO, POUPAERT JACQUES H., WOUTERS JOHAN, LAMBE: "Substituted 2-Thioxoimidazolidin-4-ones and Imidazolidine-2,4-diones as Fatty Acid Amide Hydrolase Inhibitors Templates", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 49, no. 1, 1 January 2006 (2006-01-01), US , pages 417 - 425, XP093386345, ISSN: 0022-2623, DOI: 10.1021/jm050977k *
NADIR UPENDER K., VIJAYA KRISHNA R.: "Facile cleavage of i N /i arylsulfonyl bond of i N /i ‐arylsulfonylimidazolidinone with magnesium in methanol", JOURNAL OF HETEROCYCLIC CHEMISTRY, WILEY-BLACKWELL PUBLISHING, INC., US, vol. 41, no. 5, 1 September 2004 (2004-09-01), US , pages 737 - 739, XP093386346, ISSN: 0022-152X, DOI: 10.1002/jhet.5570410514 *

Similar Documents

Publication Publication Date Title
Duffey et al. Extending the potency and lifespan of antibiotics: inhibitors of gram-negative bacterial efflux pumps
Carney et al. Restriction of the conformational dynamics of the cyclic acyldepsipeptide antibiotics improves their antibacterial activity
Laudadio et al. Natural alkaloid berberine activity against Pseudomonas aeruginosa MexXY-mediated aminoglycoside resistance: in silico and in vitro studies
Hammad et al. From phenylthiazoles to phenylpyrazoles: broadening the antibacterial spectrum toward carbapenem-resistant bacteria
AU2007276763B2 (en) Heme oxygenase inhibitors and methods of therapeutic use
US9187524B2 (en) Broad spectrum antibiotic arylomycin analogs
US11807881B2 (en) Polypeptide, fusion polypeptide, and antibiotic against gram-negative bacteria comprising same
CA2687217A1 (en) Antibiotic compounds
Lohan et al. Structure-based rational design of small α-helical peptides with broad-spectrum activity against multidrug-resistant pathogens
JP2018135334A (en) Linear peptide antibiotics
CN101801401A (en) Kinase protein binding inhibitors
EP4373487A1 (en) Coronavirus main protease inhibitors and methods using same
Saini et al. Targeting Vancomycin-Resistant Enterococci (VRE) Infections and Van Operon-Mediated Drug Resistance Using Dimeric Cholic Acid–Peptide Conjugates
JP2020536072A (en) Peptide antibiotic complex and how to use it
WO2025264672A1 (en) Inhibitors of mobilized colistin resistance enzyme (mcr-1) and methods of use thereof
US20220315624A1 (en) Thiostrepton analogs and methods of making and using same
EP3596089B1 (en) Antibacterial compounds
US20240158355A1 (en) Bet subfamily inhibitors and methods using same
US20250325542A1 (en) Inhibitors of antimocrobial resistance and methos using same
US20220112166A1 (en) Selective JAK2 Pseudokinase Ligands and Methods of Use
US20220202772A1 (en) Compositions and methods for inhibiting ribosome inactivating proteins
US10875890B2 (en) Peptide inhibitors targeting the Neisseria gonorrhoeae pivotal anaerobic respiration factor AniA
WO2020257753A1 (en) Phosphatidylserine decarboxylase inhibitors
WO2014011663A1 (en) Inhibitors of bacterial diguanylate cyclase
US12286398B2 (en) Anti-bacterial stilbene derivatives and methods of use

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 25830848

Country of ref document: EP

Kind code of ref document: A1