WO2018067465A1

WO2018067465A1 - Compositions and methods for treating drug-resistant bacteria

Info

Publication number: WO2018067465A1
Application number: PCT/US2017/054768
Authority: WO
Inventors: Feng Wang; Hui Guo
Original assignee: The California Institute For Biomedical Research
Priority date: 2016-10-03
Filing date: 2017-10-02
Publication date: 2018-04-12

Abstract

Disclosed herein are methods for treating drug-resistant bacteria using a compound of Formula (I).

Description

COMPOSITIONS AND METHODS FOR TREATING DRUG-RESISTANT BACTERIA

CROSS REFERENCE

[0001] This application claims the benefit of U.S. Provisional Patent Application Serial No. 62/403,620 filed October 3, 2016 and U.S. Provisional Patent Application Serial No. 62/517,683 filed June 9, 2017, the entirety of which are incorporated by reference herein.

BACKGROUND OF THE INVENTION

[0002] The increasing prevalence of drug resistant bacteria is a severe threat to human health worldwide. Of particular concern are bacteria such as Staphylococcus aureus, which are characterized by diverse strains having resistances against virtually all available antibiotics. Infections caused by such multi-drug resistant bacteria can lead to severe and often fatal consequences. As drug resistant bacteria are rapidly evolving, novel treatment strategies are urgently needed.

SUMMARY OF THE INVENTION

[0003] In various aspects, compounds disclosed herein are antibacterial compounds which kill or otherwise inhibit growth of drug-resistant bacteria. One such compound, avasimibe, is a known drug whose safety profile was studied during a Phase III clinical trial for treatment of cardiovascular disease in more than 1,300 patients. 50, 125, 250, or 500 mg avasimibe administered as capsules once daily for 8 weeks was well tolerated in the patients. Due to the known pharmacology and established safety profile of this drug in humans, and the antibacterial activity of avasimibe for various isolates of multi-drug resistant bacteria, avasimibe is a suitable candidate for treatment of infections caused by drug-resistant bacteria.

[0004] In one aspect, provided herein is a method of treating a bacterial infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of an antibacterial compound of Formula (I):

Formula (I)

or pharmaceutically acceptable salt or solvate thereof, wherein:

R¹ and Pv³ are independently selected from substituted or unsubstituted Ci-Ci₀alkyl, substituted or

unsubstituted C₃-Ci₀cycloalkyl, substituted or unsubstituted C₂-Ci₀heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, wherein if R¹ and R³ are substituted then R¹ and R³ are independently substituted with one or more R⁴ groups;

each R⁴ is independently selected from D, -OR⁵, -SR⁵, -F, -CI, -Br, -I, -C(0)R⁵, -C0₂R⁵, -CN, -N0₂, -

N(R⁶)(R⁷), substituted or unsubstituted Ci-C₇alkyl, substituted or unsubstituted C₃-C₇cycloalkyl, substituted or unsubstituted C₂-C₆heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

each R⁵ is independently selected from H, substituted or unsubstituted Ci-C₆alkyl, substituted or unsubstituted C₃-C₇cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

each R⁶ and R⁷ are independently selected from H, substituted or unsubstituted Ci-C₇alkyl, substituted or unsubstituted Ci-C₇fluoroalkyl, and substituted or unsubstituted Ci-C₇heteroalkyl; or R⁶ and R⁷ can optionally be taken together with the N-atom to which they are attached to form a N-containing heterocycle;

R² is independently selected from H, substituted or unsubstituted Ci-C₇alkyl, substituted or unsubstituted C₃- C₇cycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted benzyl;

X and Y are independently selected from -0-, -S-, and (-CR⁸R⁹-)_n; wherein each R⁸ and R⁹ are independently selected from H, -F, -CI, -Br, -I, -OR⁵, -C(0)R⁵, substituted or unsubstituted Ci-C₇alkyl; substituted or unsubstituted C₃-C₇cycloalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

n is 1, 2, 3, or 4.

[0005] In some embodim re of Formula (la)

Formula (la)

or pharmaceutically acceptable salt or solvate thereof, wherein:

X¹, X², X³, X⁴, and X⁵ are independently selected from Ν, CH, and CR⁴;

Y¹, Y², Y³, Y⁴, and Y⁵ are independently selected from Ν, CH, and CR⁴;

p is 0, 1, 2, 3, 4 or 5.

[0006] In some embodime structure of Formula (lb)

Formula (lb)

or pharmaceutically acceptable salt or solvate thereof, wherein:

each R⁴ is independently selected from H, substituted or unsubstituted Ci-C₇alkyl which may optionally be substituted with -F, -OH, and -OMe, and C₃-C₇cycloalkyl;

R⁸ and R⁹ are independently selected from -H and Ci-C₇alkyl or R⁴ and R⁵ are taken together to form a C₃-

C₇cycloalkyl; additionally or alternatively, one of R⁴ may be taken together with one of R⁸ or R⁹ to form a C₅-Cncycloalkyl ring.

[0007] In some embodi re of avasimibe

or pharmaceutically acceptable salt or solvate thereof.

[0008] In some embodiments, a causative agent of the bacterial infection is a Gram-positive bacteria, and the subject is infected with the causative agent. In some embodiments, the Gram-positive bacteria comprises Staphylococcus, Bacillus, Enterococcus , Streptococcus, Clostridium, or a combination thereof. In some embodiments, a causative agent of the bacterial infection is a drug -resistant bacteria, and the subject is infected with the causative agent. In some embodiments, the drug is an antibiotic. In some embodiments, the antibiotic comprises a polymyxin antibiotic, a beta-lactam antibiotic, a fluoroquinolone antibiotic, a cephalosporin antibiotic, a carbapenem antibiotic, a cephalosporin antibiotic, or a combination thereof. In some embodiments, treating the bacterial infection comprises reducing the population of viable causative agent in the subject as compared to the population of viable causative agent in the subject prior to administration of the antibacterial compound of Formula (I). In some embodiments, treating the bacterial infection comprises reducing growth, replication and/or propagation of the causative agent in the subject by at least about 20%, 40%, 60%, 80% or 90% after administration of the antibacterial compound of Formula (I). In some embodiments, the subject is administered an additional antibacterial compound. In some embodiments, the subject is administered an antibody or an antigen-binding fragment of the antibody.

[0009] In another aspect, provided herein is a method of exerting an antibacterial effect on a bacteria, the method comprising contacting the bacteria with a compound of Formula (I)

Formula (I)

or pharmaceutically acceptable salt or solvate thereof, wherein:

R¹ and R³ are independently selected from substituted or unsubstituted Ci-Ci₀alkyl, substituted or

each R⁶ and R⁷ are independently selected from H, substituted or unsubstituted Ci-C₇alkyl, substituted or unsubstituted Ci-C₇fluoroalkyl, and substituted or unsubstituted Ci-C₇heteroalkyl; or

R⁶ and R⁷ can optionally be taken together with the N-atom to which they are attached to form a N-containing heterocycle;

n is 1, 2, 3, or 4.

[0010] In some embodi cture of avasimibe

or pharmaceutically acceptable salt or solvate thereof.

[0011] In some embodiments, contacting comprises bringing the bacteria in proximity to the compound of Formula (I) such that the compound of Formula (I) exerts the antibacterial effect on the bacteria. In some embodiments, the antibacterial effect comprises: (i) killing the bacteria, (ii) reducing growth of the bacteria, (iii) reducing replication of the bacteria, (iv) reducing propagation of the bacteria, (v) reducing viable bacteria population, or (vi) a combination of any of (i)-(v). In some embodiments, the antibacterial effect is evaluated by measuring the minimal inhibitory concentration 50% (MIC50) of the compound of Formula (I) for the bacteria, and the MIC50 is less than about 50 μΜ, 40 μΜ, 30 μΜ, 20 μΜ, 10 μΜ, 1 μΜ, 100 ηΜ, 10 ηΜ, 1 ηΜ, 100 ρΜ or 10 ρΜ. In some embodiments, contacting comprises administering the compound of Formula (I) to a subject infected with the bacteria. In some embodiments, contacting comprises combining the compound of Formula (I) with the bacteria in an in vitro solution. In some embodiments, contacting comprises providing the compound of Formula (I) on a surface comprising or suspected of comprising the bacteria. In some embodiments, the bacteria has resistance to a drug.

[0012] In another aspect, provided herein is a method of identifying antibacterial activity of a compound of Formula (I) for a test bacteria, the method comprising contacting the test bacteria with a compound of Formula (I)

Formula (I)

or pharmaceutically acceptable salt or solvate thereof, wherein:

n is 1, 2, 3, or 4.

[0013] In some embodiments, the compound of Formula (I) kills and/or inhibits the test bacteria after contact, the compound of Formula (I) is identified as having antibacterial activity for the test bacteria. In some embodiments, inhibition of the test bacteria comprises (i) reducing growth of the bacteria, (ii) reducing replication of the bacteria, (iii) reducing propagation of the bacteria, (iv) reducing viable bacteria population, or (v) a combination of any of (i)-(iv). In some embodiments, contacting comprises combining the compound of Formula (I) with the test bacteria in an in vitro solution. In some embodiments, contacting comprises providing the compound of Formula (I) on a surface comprising the test bacteria. In some embodiments, contacting comprises administering the compound of Formula (I) to a subject infected with the test bacteria.

[0014] In another aspect, provided herein is a combination comprising first agent having Formula (I)

Formula (I)

or pharmaceutically acceptable salt or solvate thereof, and a second agent, wherein:

n is 1, 2, 3, or 4.

[0015] In some embodiments, the second agent comprises (i) an antibacterial compound and/or (ii) an antibody or an antigen-binding fragment of the antibody. [0016] In another aspect, provided herein is a method of treating a bacterial infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of an antibacterial compound of Formula (I)

Formula (I)

or pharmaceutically acceptable salt or solvate thereof, wherein:

n is 1, 2, 3, or 4.

[0017] In some cases, the antibacterial compound of Formula (I) has the structure of Formula (la)

Formula (la) or pharmaceutically acceptable salt or solvate thereof, wherein:

X¹, X², X³, X⁴, and X⁵ are independently selected from N, CH, and CR⁴;

Y¹, Y², Y³, Y⁴, and Y⁵ are independently selected from N, CH, and CR⁴;

p is 0, 1, 2, 3, 4 or 5.

[0018] In some cases, the antibacterial compound of Formula (la) has the structure of Formula (lb)

Formula (lb)

or pharmaceutically acceptable salt or solvate thereof, wherein:

C₇cycloalkyl;

additionally or alternatively, one of R⁴ may be taken together with one of R⁸ or R⁹ to form a C₅-CnCycloalkyl ring.

[0019] In some cases, the antibacterial compound of Formula (lb) has the structure of avasimibe

or pharmaceutically acceptable salt or solvate thereof.

[0020] In some embodiments, a causative agent of the bacterial infection is a Gram-positive bacteria, and the subject is infected with the causative agent. In some cases, the Gram-positive bacteria is selected from the genus Staphylococcus, Bacillus, Enterococcus , Streptococcus, and Clostridium. In some cases, the Gram- positive bacteria is selected from Staphylococcus aureus, Staphylococcus epidermidis, Bacillus subtilis, Enterococcus faecium, Streptococcus pneumonia, Streptococcus pyogenes, and Clostridium difficile. In some embodiments, a causative agent of the bacterial infection is a Gram-negative bacteria, and the subject is infected with the causative agent. In some cases, the Gram-negative bacteria is selected from the genus Pseudomonas, Escherichia, Haemophilus, Acinetobacter, and Klebsiella. In some cases, the Gram-negative bacteria is selected from Pseudomonas aeruginosa, Escherichia coli, Haemophilus influenzae, Acinetobacter baumannii, and Klebsiella pneumonia. In some embodiments, the Gram-positive bacteria has resistance to a drug. In some embodiments, the Gram-negative bacteria has resistance to a drug. In some embodiments, a causative agent of the bacterial infection is a bacteria having resistance to a drug. In some embodiments, the drug is an antibiotic. In some cases, the antibiotic is a polymyxin antibiotic. In some cases, the polymyxin antibiotic comprises polymyxin B and/or colistin. In some cases, the antibiotic is a beta-lactam antibiotic. In some cases, the beta-lactam antibiotic comprises penicillin, methicillin, oxacillin, nafcillin, ampicillin, amoxicillin, carbenicillin or a combination thereof. In some cases, the antibiotic is a fluoroquinolone antibiotic. In some cases, the antibiotic is a cephalosporin antibiotic. In some cases, the antibiotic is a carbapenem antibiotic. In some cases, the antibiotic is a cephalosporin antibiotic. In some cases, the antibiotic comprises methicillin, vancomycin, erythromycin, doxycycline, tetracycline, linezolid, clindamycin, ceftriazone, or a combination thereof.

[0021] In some embodiments, treating the bacterial infection comprises reducing the population of viable causative agent in the subject as compared to the population of viable causative agent in the subject prior to administration of the antibacterial compound of Formula (I). In some cases, the population of viable causative agent in the subject is reduced by at least about 20%, 40%, 60%, 80% or 90% after administration of the antibacterial compound of Formula (I). In some cases, the population of viable causative agent in the subject is reduced within 1, 2, 3, 4, 5, 6 or 7 days of a first dose of the administration of the antibacterial compound of Formula (I). In some cases, treating the bacterial infection comprises reducing growth, replication and/or propagation of the causative agent in the subject by at least about 20%, 40%, 60%, 80% or 90% after administration of the antibacterial compound of Formula (I). In some cases, the reduction in growth, replication and/or propagation of the causative agent in the subject is reduced by at least about 20%, 40%, 60%, 80% or 90% after administration of the antibacterial compound of Formula (I). In some cases, the growth, replication and/or propagation of the causative agent in the subject is reduced within 1, 2, 3, 4, 5, 6 or 7 days of a first dose of the administration of the antibacterial compound of Formula (I). In some cases, treating the bacterial infection comprises reducing a symptom and/or complication of the bacterial infection presenting in the subject, as compared to the symptom and/or complication prior to the administration of the antibacterial compound of Formula (I). In some cases, the symptom and/or complication of the bacterial infection is reduced by at least about 20%, 40%, 60%, 80% or 90%. In some cases, the symptom and/or complication of the bacterial infection is reduced within 1, 2, 3, 4, 5, 6 or 7 days of a first dose of the administration of the antibacterial compound of Formula (I).

[0022] In some embodiments, the antibacterial compound of Formula (I) is administered in one or more doses totaling 1-1,000 mg per day. In some cases, the antibacterial compound of Formula (I) is administered 1, 2, 3 or 4 times a day. In some cases, the antibacterial compound of Formula (I) is administered over a course of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 days. In some cases, the antibacterial compound of Formula (I) is intravenously administered. In some cases, the antibacterial compound of Formula (I) is administered by nasogastric or orogastric intubation. In some cases, the antibacterial compound of Formula (I) is orally administered. In some cases, the subject is administered an additional antibacterial compound. In some cases, the additional antibacterial compound is administered with the antibacterial compound of Formula (I). In some cases, the additional antibacterial compound is administered separately from the antibacterial compound of Formula (I). In some cases, the additional antibacterial compound is administered in a separate

composition than the antibacterial compound of Formula (I). In some cases, the additional antibacterial compound comprises an aminoglycoside. In some cases, the aminoglycoside comprises kanamycin, amikacin, apramycin, arbekacin, astromicin, bekanamycin, capreomycin, dibekacin, dihydrostreptomycin, elsamitrucin, fosfomycin, tobramycin, g418, gentamicin, hygromycin b, isepamicin, kanamycin, kasugamycin, legonmycin, lividomycin, micronomicin, neamine, neomycin, netilmicin, nourseothricin, paromomycin, plazomicin, ribostamycin, sisomicin, streptoduocin, streptomycin, tobramycin, totomycin, verdamicin or a combination thereof.

[0023] In some embodiments, the compound of Formula (I) is administered to treat infection of the subject with S. aureus. In some embodiments, the compound of Formula (I) is administered to prevent infection of the subject with S. aureus. In some embodiments, the compound of Formula (I) is administered prior to, during, and/or within 1 year of the subject undergoing a medical procedure. In some embodiments, the medical procedure comprises a surgery. In some embodiments, the medical procedure comprises the subject receiving an implant. In some embodiments, the implant is an orthopedic implant. In some embodiments, the orthopedic implant is a joint prosthesis, graft or synthetic implant. In some embodiments, the bacterial infection is in a bone of the subject and/or within a 1 inch region of the bone of the subject. In some embodiments, the subject has osteomyelitis. In some embodiments, the bacterial infection is a periprosthetic infection. In some embodiments, the subject is immunocompromised. In some embodiments, the subject has Human Immunodeficiency Virus (HIV) or acquired immune deficiency syndrome (AIDS).

[0024] In some embodiments, the subject is administered an antibody or an antigen-binding fragment of the antibody. In some embodiments, the antibody or the antigen-binding fragment of the antibody is administered with the antibacterial compound of Formula (I). In some embodiments, the antibody or the antigen-binding fragment of the antibody is administered separately from the antibacterial compound of Formula (I). In some embodiments, the antibody or the antigen-binding fragment of the antibody is administered in a separate composition from the antibacterial compound of Formula (I). In some embodiments, the antibody or the antigen-binding fragment of the antibody is administered as a vaccine to prevent the bacterial infection. In some embodiments, the subject is an individual who has a greater risk than the general population for developing the bacterial infection. In some embodiments, the antibody or the antigen-binding fragment of the antibody is administered during passive immunization. In some embodiments, the antibody or the antigen- binding fragment of the antibody is administered for the treatment of active bacterial infection. In some embodiments, the antibody is administered during active immunization. In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a peptide or portion thereof from a bacteria selected from Staphylococcus, Bacillus, Enterococcus , Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, and Klebsiella. In some embodiments, the antibody or the antigen-binding fragment of the antibody promotes lysis of the bacteria. In some embodiments, the bacteria is drug-resistant. In some embodiments, the bacteria is methicillin resistant. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is humanized.

[0025] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to an autolysin or fragment thereof. In some embodiments, the autolysin is from a bacteria selected from

Staphylococcus, Bacillus, Enterococcus , Streptococcus, Clostridium, Pseudomonas, Escherichia,

Haemophilus, Acinetobacter, and Klebsiella. In some embodiments, the bacteria is Stapylococcus . In some embodiments, the antibody or the antigen-binding fragment of the antibody at least partially or wholly binds to the glucosaminidase subunit of the autolysin, or a fragment of the glucosaminidase subunit. In some embodiments, the glucosaminidase comprises the sequence of SEQ ID NO: 1. In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to an epitope at least partially positioned within the glucosaminidase R3 domain. In some embodiments, the glucosaminidase is a Staphylococcus aureus glucosaminidase. In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to an epitope within the glucosaminidase catalytic domain. In some embodiments, the antibody or the antigen-binding fragment of the antibody inhibits activity of the glucosaminidase. In some embodiments, the antibody or the antigen-binding fragment of the antibody comprises a variable domain sequence at least 80%, 85%, 90%, 95%, or 99% homologous to a sequence selected from SEQ ID NO: 2-13. In some embodiments, the antibody or the antigen-binding fragment of the antibody comprises one or more CDRs selected from SEQ ID NOS: 2-13. In some embodiments, the antibody or the antigen-binding fragment of the antibody comprises the sequences of amino acid residues 31 -35, 50-66, and 99-1 10 of SEQ ID NO: 6 and/or the sequence of amino acid residues 24-31, 50-56, and 89-95 of SEQ ID NO: 1 1.

[0026] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a bacterial autolysin N-acetylmuramoyl-L-alanine amidase catalytic domain or a fragment or portion thereof. In some embodiments, the bacterial autolysin N-acetylmuramoyl-L-alanine amidase catalytic domain is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

[0027] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a bacterial cell wall binding domain, or a fragment or portion thereof. In some embodiments, the bacterial cell wall binding domain is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

[0028] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a bacterial cell surface-associated antigen, or a fragment or portion thereof. In some embodiments, the bacterial cell surface -associated antigen is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

[0029] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a bacterial exotoxin, or a fragment or portion thereof. In some embodiments, the bacterial exotoxin is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus , Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

[0030] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a bacterial protease, or a fragment or portion thereof. In some embodiments, the bacterial protease is V8 protease, a member of the glutamyl endopeptidase I family of Staphylococcus aureus V8 strain (GluV8), or a fragment or portion thereof. In some embodiments, the bacterial protease is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia,

Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

[0031] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a bacterial leucocidin, or a fragment or portion thereof. In some embodiments, the bacterial leucocidin is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

[0032] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a bacterial adhesin, or a fragment or portion thereof. In some embodiments, the bacterial adhesin is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof. In some embodiments, the bacterial adhesin is a surface-bound adhesin that promotes host colonization.

[0033] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a cell surface adhesin that interacts with an extracellular matrix component (microbial surface component recognizing adhesive matrix molecules or MSCRAMMs), or a fragment or portion thereof.

[0034] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to lipoteichoic acid (LTA), or a fragment or portion thereof. In some embodiments, the antibody is pagibaximab

(BSYX-A1 10).

[0035] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to

Clumping Factor A (ClfA), or a fragment or portion thereof. In some embodiments, the antibody is tefibazumab. In some embodiments, the antibody is Veronate.

[0036] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to ATP- binding cassette (ABC) transporter component GrfA, or a fragment or portion thereof. In some embodiments, the antibody is Aurograb.

[0037] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to poly-N- acetylated glucosamine (PNAG) , or a fragment or portion thereof. In some embodiments, the antibody is SAR279356 (F598).

[0038] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to alpha- toxin (AT), or a fragment or portion thereof. In some embodiments, the antibody is MEDI4893. In some embodiments, the antibody is AR-301.

[0039] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a bacterial molecule selected from an amidase (Amd) protein or polypeptide, an iron-regulated surface determinant protein A (IsdA) protein or polypeptide, an iron-regulated surface determinant protein B (IsdB) protein or polypeptide, an iron-regulated surface determinant protein H (IsdH) protein or polypeptide, a Clumping Factor A (ClfA) protein or polypeptide, a Clumping Factor B (ClfB) protein or polypeptide, a Fibronectin Binding Protein A (FnbpA) protein or polypeptide, a Staphylococcus Complement Inhibitor (SCIN) protein or polypeptide, a Chemotaxis Inhibitory Protein of Staphylococcus aureus (CHIPS) protein or polypeptide, an alpha-Hemolysin (Hla) protein or polypeptide, an Extracellular Fibrinogen-binding (Efb) protein or polypeptide, S pro-toxin subunit from Staphylococcus (LukS-PV) protein or polypeptide, Ser-Asp dipeptide repeat G from (SdrG) protein or polypeptide, staphylococcal enteroxin B (SEB) protein or polypeptide, N-terminus of the candidal surface adhesin (rAls3p-N) protein or polypeptide, extracellular adherence protein (Eap) protein or polypeptide, Serine aspartate repeat containing protein D (SdrD) protein or polypeptide, Serine aspartate repeat containing protein E (SdrE) protein or polypeptide, staphylococcal antigen A (IsaA) protein or polypeptide, protein A or a polypeptide of protein A, panton-valentine leucocidin (PVL) protein or polypeptide, γ-hemolysin C (HlgC) protein or polypeptide, Ferric hydroxamate-binding lipoprotein (FhuD2) protein or polypeptide, capsular polysaccharide type 5, capsular polysaccharide type 8; or a combination, fragment and/or portion thereof. In some embodiments, the bacterial molecule is from Staphylococcus. In some embodiments, the bacterial molecule is from Staphylococcus aureus.

[0040] In some embodiments, the antibody is selected from Altastaph, Veronate, Aurexis (tefibazumab), pagibaximab (BSYX-A1 10), Aurograb, SAR279356 (F598), MEDI4893, Salvecin (AR-301, KBSA301), and 514G3 (XBiotech). In some embodiments, the antigen-binding fragment is from an antibody selected from Altastaph, Veronate, Aurexis (tefibazumab), pagibaximab (BSYX-A1 10), Aurograb, SAR279356 (F598), MEDI4893, Salvecin (AR-301, KBSA301), and 514G3 (XBiotech).

[0041] In some embodiments, the antibody or the antigen-binding fragment of the antibody comprises a variable domain and/or one or more CDRs from SEQ ID NOS: 14-23.

[0042] In another aspect, provided herein is method of exerting an antibacterial effect on a bacteria, the method comprising contacting the bacteria with a compound of Formula (I)

Formula (I)

or pharmaceutically acceptable salt or solvate thereof, wherein:

unsubstituted C₃-Ci₀cycloalkyl, substituted or unsubstituted C₂-Ci₀heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, wherein if R¹ and R³ are substituted then R¹ and R³ are independently substituted with one or more R⁴ groups; each R⁴ is independently selected from D, -OR⁵, -SR⁵, -F, -CI, -Br, -I, -C(0)R⁵, -C0₂R⁵, -CN, -N0₂, -

n is 1, 2, 3, or 4.

[0043] In some cases, the compound of Formula (I) has the structure of Formula (la)

Formula (la)

or pharmaceutically acceptable salt or solvate thereof, wherein:

p is 0, 1, 2, 3, 4 or 5.

[0044] In some cases, the compound of Formula (la) has the structure of Formula (lb)

Formula (lb)

or pharmaceutically acceptable salt or solvate thereof, wherein:

each R⁴ is independently selected from H, substituted or unsubstituted Ci-C₇alkyl which may optionally be substituted with -F, -OH, and -OMe, and C₃-C₇cycloalkyl; R⁸ and R⁹ are independently selected from -H and Ci-C₇alkyl or R⁴ and R⁵ are taken together to form a C₃- C₇cycloalkyl;

[0045] In some cases, the compound of Formula (lb) has the structure of avasimibe

or pharmaceutically acceptable salt or solvate thereof.

[0046] In some cases, contacting comprises bringing the bacteria in proximity to the compound of Formula (I) such that the compound of Formula (I) exerts the antibacterial effect on the bacteria. In some cases, the antibacterial effect comprises: (i) killing the bacteria, (ii) reducing growth of the bacteria, (iii) reducing replication of the bacteria, (iv) reducing propagation of the bacteria, (v) reducing viable bacteria population, or (vi) a combination of any of (i)-(v). In some cases, the antibacterial effect is evaluated by measuring the minimal inhibitory concentration 50% (MIC50) of the compound of Formula (I) for the bacteria. In some cases, the MIC50 is less than about 50 μΜ, 40 μΜ, 30 μΜ, 20 μΜ, 10 μΜ, 1 μΜ, 100 ηΜ, 10 nM, 1 ηΜ, 100 ρΜ or 10 ρΜ. In some cases, contacting comprises administering the compound of Formula (I) to a subject infected with the bacteria. In some cases, the compound of Formula (I) is administered orally, intravenously, subcutaneously or by nasogastric or orogastric intubation. In some cases, the subject is a human subject or a non-human animal subject. In some cases, the non-human animal is a mouse. In some cases, contacting comprises combining the compound of Formula (I) with the bacteria in an in vitro solution. In some cases, contacting comprises providing the compound of Formula (I) on a surface comprising or suspected of comprising the bacteria. In some cases, the bacteria is a Gram-negative bacteria. In some cases, the Gram- negative bacteria is selected from the genus Pseudomonas, Escherichia, Haemophilus, Acinetobacter, and Klebsiella. In some cases, the Gram-negative bacteria is selected from Pseudomonas aeruginosa, Escherichia coli, Haemophilus influenzae, Acinetobacter baumannii, and Klebsiella pneumonia. In some cases, the bacteria is a Gram-positive bacteria. In some cases, the Gram-positive bacteria is selected from the genus Staphylococcus, Bacillus, Enterococcus , Streptococcus, and Clostridium. In some cases, the Gram-positive bacteria is selected from Staphylococcus aureus, Staphylococcus epidermidis, Bacillus subtilis, Enterococcus faecium, Streptococcus pneumonia, Streptococcus pyogenes, and Clostridium difficile. In some cases, the bacteria has resistance to a drug. In some cases, the drug is an antibiotic. In some cases, the antibiotic is a polymyxin antibiotic. In some cases, the polymyxin antibiotic comprises polymyxin B and/or colistin. In some cases, the antibiotic is a beta-lactam antibiotic. In some cases, the beta-lactam antibiotic comprises penicillin, methicillin, oxacillin, nafcillin, ampicillin, amoxicillin, carbenicillin or a combination thereof. In some cases, the antibiotic is a fluoroquinolone antibiotic. In some cases, the antibiotic is a cephalosporin antibiotic. In some cases, the antibiotic is a carbapenem antibiotic. In some cases, the antibiotic is a cephalosporin antibiotic. In some cases, the antibiotic comprises methicillin, vancomycin, erythromycin, doxycycline, tetracycline, linezolid, clindamycin, ceftriazone, or a combination thereof. In some cases, the method further comprises contacting the bacteria with an antibacterial compound. In some cases, the antibacterial compound comprises an aminoglycoside. In some cases, the aminoglycoside comprises kanamycin, amikacin, apramycin, arbekacin, astromicin, bekanamycin, capreomycin, dibekacin,

dihydrostreptomycin, elsamitrucin, fosfomycin, tobramycin, g418, gentamicin, hygromycin b, isepamicin, kanamycin, kasugamycin, legonmycin, lividomycin, micronomicin, neamine, neomycin, netilmicin, nourseothricin, paromomycin, plazomicin, ribostamycin, sisomicin, streptoduocin, streptomycin, tobramycin, totomycin, verdamicin or a combination thereof.

[0047] In some embodiments, the bacteria is S. aureus. In some embodiments, the method further comprises contacting the bacteria with an antibody or an antigen-binding fragment of the antibody. In some

embodiments, the bacteria is contacted with the antibody or the antigen-binding fragment of the antibody prior to contacting the bacteria with the antibacterial compound of Formula (I). In some embodiments, the bacteria is contacted with the antibody or the antigen-binding fragment of the antibody after contacting the bacteria with the antibacterial compound of Formula (I). In some embodiments, the antibody or the antigen-binding fragment of the antibody contacts the bacteria separately from the antibacterial compound of Formula (I). In some embodiments, the antibody or the antigen-binding fragment of the antibody prevents infection, growth, or propagation of the bacteria. In some embodiments, the antibody or the antigen-binding fragment of the antibody promotes lysis of the bacteria. In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a peptide or portion thereof from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, and Klebsiella. In some embodiments, the bacteria to which the antibody or the antigen-binding fragment of the antibody binds is drug-resistant. In some embodiments, the drug-resistant bacteria is resistant to methicillin. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is humanized.

[0048] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to an autolysin or fragment thereof. In some embodiments, the autolysin is from a bacteria selected from

Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia,

Haemophilus, Acinetobacter, and Klebsiella. In some embodiments, the autolysin is from Stapylococcus . In some embodiments, the antibody or the antigen-binding fragment of the antibody at least partially or wholly binds to the glucosaminidase subunit of the autolysin, or a fragment of the glucosaminidase subunit. In some embodiments, the glucosaminidase comprises the sequence of SEQ ID NO: 1. In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to an epitope at least partially positioned within the glucosaminidase R3 domain. In some embodiments, the glucosaminidase is a Staphylococcus aureus glucosaminidase. In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to an epitope within the glucosaminidase catalytic domain. In some embodiments, the antibody or the antigen-binding fragment of the antibody inhibits activity of the glucosaminidase. In some embodiments, the antibody or the antigen-binding fragment of the antibody comprises a variable domain sequence at least 80%, 85%, 90%, 95%, or 99% homologous to a sequence selected from SEQ ID NO: 2-13. In some embodiments, the antibody or the antigen-binding fragment of the antibody comprises one or more CDRs selected from SEQ ID NOS: 2-13. In some embodiments, the antibody or the antigen-binding fragment of the antibody comprises the sequences of amino acid residues 31 -35, 50-66, and 99-1 10 of SEQ ID NO: 6 and/or the sequence of amino acid residues 24-31, 50-56, and 89-95 of SEQ ID NO: 1 1.

[0049] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a bacterial autolysin N-acetylmuramoyl-L-alanine amidase catalytic domain or a fragment or portion thereof. In some embodiments, the bacterial autolysin N-acetylmuramoyl-L-alanine amidase catalytic domain is from a bacteria selected from Staphylococcus, Bacillus, Enter ococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

[0050] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a bacterial cell wall binding domain, or a fragment or portion thereof. In some embodiments, the bacterial cell wall binding domain is from a bacteria selected from Staphylococcus, Bacillus, Enter ococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

[0051] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a bacterial cell surface-associated antigen, or a fragment or portion thereof. In some embodiments, the bacterial cell surface -associated antigen is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

[0052] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a bacterial exotoxin, or a fragment or portion thereof. In some embodiments, the bacterial exotoxin is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

[0053] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a bacterial protease, or a fragment or portion thereof. In some embodiments, the bacterial protease is V8 protease, a member of the glutamyl endopeptidase I family of Staphylococcus aureus V8 strain (GluV8), or a fragment or portion thereof. In some embodiments, the bacterial protease is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia,

Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

[0054] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a bacterial leucocidin, or a fragment or portion thereof. In some embodiments, the bacterial leucocidin is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof. [0055] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a bacterial adhesin, or a fragment or portion thereof. In some embodiments, the bacterial adhesin is from a bacteria selected from Staphylococcus, Bacillus, Enter ococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof. In some embodiments, the bacterial adhesin is a surface-bound adhesin that promotes host colonization.

[0056] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a cell surface adhesin that interacts with an extracellular matrix component (microbial surface component recognizing adhesive matrix molecules or MSCRAMMs), or a fragment or portion thereof.

[0057] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to lipoteichoic acid (LTA), or a fragment or portion thereof. In some embodiments, the antibody is pagibaximab

(BSYX-A1 10).

[0058] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to

[0059] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to ATP- binding cassette (ABC) transporter component GrfA, or a fragment or portion thereof. In some embodiments, the antibody is Aurograb.

[0060] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to poly-N- acetylated glucosamine (PNAG) , or a fragment or portion thereof. In some embodiments, the antibody is SAR279356 (F598).

[0061] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to alpha- toxin (AT), or a fragment or portion thereof. In some embodiments, the antibody is MEDI4893. In some embodiments, the antibody is AR-301.

[0062] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a bacterial molecule selected from an amidase (Amd) protein or polypeptide, an iron-regulated surface determinant protein A (IsdA) protein or polypeptide, an iron-regulated surface determinant protein B (IsdB) protein or polypeptide, an iron-regulated surface determinant protein H (IsdH) protein or polypeptide, a Clumping Factor A (ClfA) protein or polypeptide, a Clumping Factor B (ClfB) protein or polypeptide, a Fibronectin Binding Protein A (FnbpA) protein or polypeptide, a Staphylococcus Complement Inhibitor (SCIN) protein or polypeptide, a Chemotaxis Inhibitory Protein of Staphylococcus aureus (CHIPS) protein or polypeptide, an alpha-Hemolysin (Hla) protein or polypeptide, an Extracellular Fibrinogen-binding (Efb) protein or polypeptide, S pro-toxin subunit from Staphylococcus (LukS-PV) protein or polypeptide, Ser-Asp dipeptide repeat G from (SdrG) protein or polypeptide, staphylococcal enteroxin B (SEB) protein or polypeptide, N-terminus of the candidal surface adhesin (rAls3p-N) protein or polypeptide, extracellular adherence protein (Eap) protein or polypeptide, Serine aspartate repeat containing protein D (SdrD) protein or polypeptide, Serine aspartate repeat containing protein E (SdrE) protein or polypeptide, staphylococcal antigen A (IsaA) protein or polypeptide, protein A or a polypeptide of protein A, panton-valentine leucocidin (PVL) protein or polypeptide, γ-hemolysin C (HlgC) protein or polypeptide, Ferric hydroxamate-binding lipoprotein (FhuD2) protein or polypeptide, capsular polysaccharide type 5, capsular polysaccharide type 8; or a combination, fragment and/or portion thereof. In some embodiments, the bacterial molecule is from Staphylococcus. In some embodiments, the bacterial molecule is from Staphylococcus aureus.

[0063] In some embodiments, the antibody or the antigen binding fragment of the antibody is selected from Altastaph, Veronate, Aurexis (tefibazumab), pagibaximab (BSYX-A110), Aurograb, SAR279356 (F598), MEDI4893, Salvecin (AR-301, KBSA301), and 514G3 (XBiotech).

[0064] In some embodiments, the antibody or the antigen-binding fragment of the antibody comprises a variable domain and/or one or more CDRs from SEQ ID NOS: 14-23.

[0065] In another aspect, provided herein is a method of identifying antibacterial activity of a compound of Formula (I) for a test bacteria, the method comprising contacting the test bacteria with a compound of Formula (I)

Formula (I)

or pharmaceutically acceptable salt or solvate thereof, wherein:

n is 1, 2, 3, or 4.

[0066] In some cases, the compound of Formula (I) has the structure of Formula (la)

Formula (la)

or pharmaceutically acceptable salt or solvate thereof, wherein:

X¹, X², X³, X⁴, and X⁵ are independently selected from N, CH, and CR⁴;

Y¹, Y², Y³, Y⁴, and Y⁵ are independently selected from N, CH, and CR⁴;

p is 0, 1, 2, 3, 4 or 5.

[0067] In some cases, the compound of Formula (la) has the structure of Formula (lb)

Formula (lb)

or pharmaceutically acceptable salt or solvate thereof, wherein:

C₇cycloalkyl;

[0068] In some cases, the compound of Formula (lb) has the structure of avasimibe

or pharmaceutically acceptable salt or solvate thereof. [0069] In some cases, wherein if the compound of Formula (I) kills or inhibits the test bacteria after contact, the compound of Formula (I) is identified as having antibacterial activity for the test bacteria. In some cases, inhibition of the test bacteria comprises (i) reducing growth of the bacteria, (ii) reducing replication of the bacteria, (iii) reducing propagation of the bacteria, (iv) reducing viable bacteria population, or (v) a combination of any of (i)-(iv). In some cases, the antibacterial activity is evaluated by measuring the minimal inhibitory concentration 50% (MIC50) of the compound of Formula (I) for the test bacteria. In some cases, if the MIC50 is less than about 50 μΜ, 40 μΜ, 30 μΜ, 20 μΜ, 10 μΜ, 1 μΜ, 100 ηΜ, 10 nM, 1 ηΜ, 100 pM or 10 pM, the compound of Formula (I) is identified as having antibacterial activity for the test bacteria. In some cases, contacting comprises bringing the test bacteria in proximity to the compound of Formula (I) such that if the compound of Formula (I) has antibacterial activity for the test bacteria, the antibacterial activity is provided. In some cases, contacting comprises combining the compound of Formula (I) with the test bacteria in an in vitro solution. In some cases, contacting comprises providing a solution comprising the test bacteria, and adding to the solution the compound of Formula (I). In some cases, contacting comprises providing a solution comprising the compound of Formula (I), and adding to the solution the test bacteria. In some cases, contacting comprises providing the compound of Formula (I) on a surface comprising the test bacteria. In some cases, contacting comprises administering the compound of Formula (I) to a subject infected with the test bacteria. In some cases, the compound of Formula (I) is administered orally, intravenously,

subcutaneously or by nasogastric or orogastric intubation. In some cases, the subject is a human subject or a non-human animal subject. In some cases, the non-human animal is a mouse. In some cases, the test bacteria is a Gram-positive bacteria. In some cases, the Gram-positive bacteria is selected from the genus

Staphylococcus, Bacillus, Enterococcus , Streptococcus, and Clostridium. In some cases, the Gram-positive bacteria is selected from Staphylococcus aureus, Staphylococcus epidermidis, Bacillus subtilis, Enterococcus faecium, Streptococcus pneumonia, Streptococcus pyogenes, and Clostridium difficile. In some cases, the test bacteria is a Gram-negative bacteria. In some cases, the Gram-negative bacteria is selected from the genus Pseudomonas, Escherichia, Haemophilus, Acinetobacter, and Klebsiella. In some cases, the Gram-negative bacteria is selected from Pseudomonas aeruginosa, Escherichia coli, Haemophilus influenzae, Acinetobacter baumannii, and Klebsiella pneumonia. In some cases, the test bacteria has resistance to a drug. In some cases, the drug is an antibiotic. In some cases, the antibiotic is a polymyxin antibiotic. In some cases, polymyxin antibiotic comprises polymyxin B and/or colistin. In some cases, the antibiotic is a beta-lactam antibiotic. In some cases, the beta-lactam antibiotic comprises penicillin, methicillin, oxacillin, nafcillin, ampicillin, amoxicillin, carbenicillin or a combination thereof. In some cases, the antibiotic is a fluoroquinolone antibiotic. In some cases, the antibiotic is a cephalosporin antibiotic. In some cases, the antibiotic is a carbapenem antibiotic. In some cases, the antibiotic is a cephalosporin antibiotic. In some cases, the antibiotic comprises methicillin, vancomycin, erythromycin, doxycycline, tetracycline, linezolid, clindamycin, ceftriazone, or a combination thereof. In some cases, the method further comprises contacting the bacteria with an antibacterial compound. In some cases, the antibacterial compound comprises an aminoglycoside. In some cases, the aminoglycoside comprises kanamycin, amikacin, apramycin, arbekacin, astromicin, bekanamycin, capreomycin, dibekacin, dihydrostreptomycin, elsamitrucin, fosfomycin, tobramycin, g418, gentamicin, hygromycin b, isepamicin, kanamycin, kasugamycin, legonmycin, lividomycin, micronomicin, neamine, neomycin, netilmicin, nourseothricin, paromomycin, plazomicin, ribostamycin, sisomicin, streptoduocin, streptomycin, tobramycin, totomycin, verdamicin or a combination thereof. Further provided herein is a method of treating a bacterial infection in an individual in need thereof, the method comprising administering to the individual a compound identified as having antibacterial activity as described herein.

[0070] In some embodiments, the test bacteria is S. aureus. In some embodiments, the method further comprises contacting the test bacteria with an antibody or an antigen-binding fragment of the antibody. In some embodiments, the test bacteria is contacted with the antibody or the antigen-binding fragment of the antibody prior to contacting the bacteria with the antibacterial compound of Formula (I). In some embodiments, the test bacteria is contacted with the antibody or the antigen-binding fragment of the antibody after contacting the bacteria with the antibacterial compound of Formula (I). In some embodiments, the antibody or the antigen-binding fragment of the antibody contacts the test bacteria separately from the antibacterial compound of Formula (I). In some embodiments, the antibody or the antigen-binding fragment of the antibody prevents infection, growth, or propagation of the test bacteria. In some embodiments, the antibody or the antigen-binding fragment of the antibody promotes lysis of the test bacteria. In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a peptide or portion thereof from a bacteria selected from Staphylococcus, Bacillus, Enter ococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, and Klebsiella. In some embodiments, the bacteria to which the antibody or the antigen-binding fragment of the antibody binds is drug-resistant. In some embodiments, the drug-resistant bacteria is resistant to methicillin. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is humanized.

[0071] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to an autolysin or fragment thereof. In some embodiments, the autolysin is from a bacteria selected from

Haemophilus, Acinetobacter, and Klebsiella. In some embodiments, the autolysin is from Stapylococcus . In some embodiments, the antibody or the antigen-binding fragment of the antibody at least partially or wholly binds to the glucosaminidase subunit of the autolysin, or a fragment of the glucosaminidase subunit. In some embodiments, the glucosaminidase comprises the sequence of SEQ ID NO: 1. In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to an epitope at least partially positioned within the glucosaminidase R3 domain. In some embodiments, the glucosaminidase is a Staphylococcus aureus glucosaminidase. In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to an epitope within the glucosaminidase catalytic domain. In some embodiments, the antibody or the antigen-binding fragment of the antibody inhibits activity of the glucosaminidase. In some embodiments, the antibody or the antigen-binding fragment of the antibody comprises a variable domain sequence at least 80%, 85%, 90%, 95%, or 99% homologous to a sequence selected from SEQ ID NO: 2-13. In some embodiments, the antibody or the antigen-binding fragment of the antibody comprises one or more CDRs selected from SEQ ID NOS: 2-13. In some embodiments, the antibody or the antigen-binding fragment of the antibody comprises the sequences of amino acid residues 31-35, 50-66, and 99-110 of SEQ ID NO: 6 and/or the sequence of amino acid residues 24-31, 50-56, and 89-95 of SEQ ID NO: 11.

[0072] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a bacterial autolysin N-acetylmuramoyl-L-alanine amidase catalytic domain or a fragment or portion thereof. In some embodiments, the bacterial autolysin N-acetylmuramoyl-L-alanine amidase catalytic domain is from a bacteria selected from Staphylococcus, Bacillus, Enter ococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

[0073] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a bacterial cell wall binding domain, or a fragment or portion thereof. In some embodiments, the bacterial cell wall binding domain is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

[0074] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a bacterial cell surface-associated antigen, or a fragment or portion thereof. In some embodiments, the bacterial cell surface -associated antigen is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

[0075] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a bacterial exotoxin, or a fragment or portion thereof. In some embodiments, the bacterial exotoxin is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

[0076] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a bacterial protease, or a fragment or portion thereof. In some embodiments, the bacterial protease is V8 protease, a member of the glutamyl endopeptidase I family of Staphylococcus aureus V8 strain (GluV8), or a fragment or portion thereof. In some embodiments, the bacterial protease is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia,

Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

[0077] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a bacterial leucocidin, or a fragment or portion thereof. In some embodiments, the bacterial leucocidin is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

[0078] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a bacterial adhesin, or a fragment or portion thereof. In some embodiments, the bacterial adhesin is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof. In some embodiments, the bacterial adhesin is a surface-bound adhesin that promotes host colonization. [0079] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a cell surface adhesin that interacts with an extracellular matrix component (microbial surface component recognizing adhesive matrix molecules or MSCRAMMs), or a fragment or portion thereof.

[0080] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to lipoteichoic acid (LTA), or a fragment or portion thereof. In some embodiments, the antibody is pagibaximab

(BSYX-A1 10).

[0081] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to

[0082] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to ATP- binding cassette (ABC) transporter component GrfA, or a fragment or portion thereof. In some embodiments, the antibody is Aurograb.

[0083] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to poly-N- acetylated glucosamine (PNAG) , or a fragment or portion thereof. In some embodiments, the antibody is SAR279356 (F598).

[0084] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to alpha- toxin (AT), or a fragment or portion thereof. In some embodiments, the antibody is MEDI4893. In some embodiments, the antibody is AR-301.

[0085] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a bacterial molecule selected from an amidase (Amd) protein or polypeptide, an iron-regulated surface determinant protein A (IsdA) protein or polypeptide, an iron-regulated surface determinant protein B (IsdB) protein or polypeptide, an iron-regulated surface determinant protein H (IsdH) protein or polypeptide, a Clumping Factor A (ClfA) protein or polypeptide, a Clumping Factor B (ClfB) protein or polypeptide, a Fibronectin Binding Protein A (FnbpA) protein or polypeptide, a Staphylococcus Complement Inhibitor (SCIN) protein or polypeptide, a Chemotaxis Inhibitory Protein of Staphylococcus aureus (CHIPS) protein or polypeptide, an alpha-Hemolysin (Hla) protein or polypeptide, an Extracellular Fibrinogen-binding (Efb) protein or polypeptide, S pro-toxin subunit from Staphylococcus (LukS-PV) protein or polypeptide, Ser-Asp dipeptide repeat G from (SdrG) protein or polypeptide, staphylococcal enteroxin B (SEB) protein or polypeptide, N-terminus of the candidal surface adhesin (rAls3p-N) protein or polypeptide, extracellular adherence protein (Eap) protein or polypeptide, Serine aspartate repeat containing protein D (SdrD) protein or polypeptide, Serine aspartate repeat containing protein E (SdrE) protein or polypeptide, staphylococcal antigen A (IsaA) protein or polypeptide, protein A or a polypeptide of protein A, panton-valentine leucocidin (PVL) protein or polypeptide, γ-hemolysin C (HlgC) protein or polypeptide, Ferric hydroxamate-binding lipoprotein (FhuD2) protein or polypeptide, capsular polysaccharide type 5, capsular polysaccharide type 8; or a combination, fragment and/or portion thereof. In some embodiments, the bacterial molecule is from Staphylococcus. In some embodiments, the bacterial molecule is from Staphylococcus aureus. [0086] In some embodiments, the antibody or the antigen binding fragment of the antibody is selected from Altastaph, Veronate, Aurexis (tefibazumab), pagibaximab (BSYX-Al lO), Aurograb, SAR279356 (F598), MEDI4893, Salvecin (AR-301, KBSA301), and 514G3 (XBiotech).

[0087] In some embodiments, the antibody or the antigen-binding fragment of the antibody comprises a variable domain and/or one or more CDRs from SEQ ID NOS: 14-23.

[0088] In another aspect, provided herein is a combination comprising an antibacterial compound and a compound a compound of Formula (I)

Formula (I)

or pharmaceutically acceptable salt or solvate thereof, wherein:

n is 1, 2, 3, or 4.

[0089] In some cases, the compound of Formula (I) has the structure of Formula (la)

Formula (la)

or pharmaceutically acceptable salt or solvate thereof, wherein:

X¹, X², X³, X⁴, and X⁵ are independently selected from N, CH, and CR⁴;

Y¹, Y², Y³, Y⁴, and Y⁵ are independently selected from N, CH, and CR⁴;

p is 0, 1, 2, 3, 4 or 5.

[0090] In some cases, the compound of Formula (la) has the structure of Formula (lb)

Formula (lb)

or pharmaceutically acceptable salt or solvate thereof, wherein:

C₇cycloalkyl;

[0091] In some cases, the compound of Formula (lb) has the structure of avasimibe

or pharmaceutically acceptable salt or solvate thereof.

[0092] In some cases, the antibacterial compound comprises an aminoglycoside. In some cases, the aminoglycoside comprises kanamycin, amikacin, apramycin, arbekacin, astromicin, bekanamycin, capreomycin, dibekacin, dihydrostreptomycin, elsamitrucin, fosfomycin, tobramycin, g418, gentamicin, hygromycin b, isepamicin, kanamycin, kasugamycin, legonmycin, lividomycin, micronomicin, neamine, neomycin, netilmicin, nourseothricin, paromomycin, plazomicin, ribostamycin, sisomicin, streptoduocin, streptomycin, tobramycin, totomycin, verdamicin or a combination thereof. In some cases, the antibacterial compound and the compound of Formula (I) are formulated in a composition. In some cases, the antibacterial compound and the compound of Formula (I) are formulated in separate compositions. In some cases, the antibacterial compound is formulated for oral administration, intravenous administration or administration by nasogastric or orogastric intubation. In some cases, the compound of Formula (I) is formulated for oral administration, intravenous administration or administration by nasogastric or orogastric intubation. In some cases, the antibacterial compound is formulated in a tablet, pill, gel-cap, or liquid. In some cases, the compound of Formula (I) is formulated in a tablet, pill, gel-cap, or liquid. Further provided herein is a method of treating a bacterial infection in a subject in need thereof, the method comprising administering to the subject the combination described herein.

[0093] In some embodiments, the combination further comprises an antibody or an antigen-binding fragment of the antibody. In some embodiments, the antibody or the antigen-binding fragment of the antibody is formulated in a composition with the antibacterial compound of Formula (I). In some embodiments, the antibody or the antigen-binding fragment of the antibody is not formulated in a composition with the antibacterial compound of Formula (I). In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a peptide or portion thereof from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, and Klebsiella. In some embodiments, the bacteria to which the antibody or the antigen-binding fragment of the antibody binds is drug-resistant. In some embodiments, the drug-resistant bacteria is resistant to methicillin. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is humanized.

[0094] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to an autolysin or fragment thereof. In some embodiments, the autolysin is from a bacteria selected from

[0095] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a bacterial autolysin N-acetylmuramoyl-L-alanine amidase catalytic domain or a fragment or portion thereof. In some embodiments, the bacterial autolysin N-acetylmuramoyl-L-alanine amidase catalytic domain is from a bacteria selected from Staphylococcus, Bacillus, Enter ococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

[0096] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a bacterial cell wall binding domain, or a fragment or portion thereof. In some embodiments, the bacterial cell wall binding domain is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

[0097] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a bacterial cell surface-associated antigen, or a fragment or portion thereof. In some embodiments, the bacterial cell surface -associated antigen is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

[0098] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a bacterial exotoxin, or a fragment or portion thereof. In some embodiments, the bacterial exotoxin is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

[0099] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a bacterial protease, or a fragment or portion thereof. In some embodiments, the bacterial protease is V8 protease, a member of the glutamyl endopeptidase I family of Staphylococcus aureus V8 strain (GluV8), or a fragment or portion thereof. In some embodiments, the bacterial protease is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia,

Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

[00100] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a bacterial leucocidin, or a fragment or portion thereof. In some embodiments, the bacterial leucocidin is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

[00101] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a bacterial adhesin, or a fragment or portion thereof. In some embodiments, the bacterial adhesin is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof. In some embodiments, the bacterial adhesin is a surface-bound adhesin that promotes host colonization. [00102] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a cell surface adhesin that interacts with an extracellular matrix component (microbial surface component recognizing adhesive matrix molecules or MSCRAMMs), or a fragment or portion thereof.

[00103] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to lipoteichoic acid (LTA), or a fragment or portion thereof. In some embodiments, the antibody is pagibaximab

(BSYX-A1 10).

[00104] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to

[00105] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to ATP- binding cassette (ABC) transporter component GrfA, or a fragment or portion thereof. In some embodiments, the antibody is Aurograb.

[00106] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to poly-N- acetylated glucosamine (PNAG) , or a fragment or portion thereof. In some embodiments, the antibody is SAR279356 (F598).

[00107] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to alpha- toxin (AT), or a fragment or portion thereof. In some embodiments, the antibody is MEDI4893. In some embodiments, the antibody is AR-301.

[00108] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a bacterial molecule selected from an amidase (Amd) protein or polypeptide, an iron-regulated surface determinant protein A (IsdA) protein or polypeptide, an iron-regulated surface determinant protein B (IsdB) protein or polypeptide, an iron-regulated surface determinant protein H (IsdH) protein or polypeptide, a Clumping Factor A (ClfA) protein or polypeptide, a Clumping Factor B (ClfB) protein or polypeptide, a Fibronectin Binding Protein A (FnbpA) protein or polypeptide, a Staphylococcus Complement Inhibitor (SCIN) protein or polypeptide, a Chemotaxis Inhibitory Protein of Staphylococcus aureus (CHIPS) protein or polypeptide, an alpha-Hemolysin (Hla) protein or polypeptide, an Extracellular Fibrinogen-binding (Efb) protein or polypeptide, S pro-toxin subunit from Staphylococcus (LukS-PV) protein or polypeptide, Ser-Asp dipeptide repeat G from (SdrG) protein or polypeptide, staphylococcal enteroxin B (SEB) protein or polypeptide, N-terminus of the candidal surface adhesin (rAls3p-N) protein or polypeptide, extracellular adherence protein (Eap) protein or polypeptide, Serine aspartate repeat containing protein D (SdrD) protein or polypeptide, Serine aspartate repeat containing protein E (SdrE) protein or polypeptide, staphylococcal antigen A (IsaA) protein or polypeptide, protein A or a polypeptide of protein A, panton-valentine leucocidin (PVL) protein or polypeptide, γ-hemolysin C (HlgC) protein or polypeptide, Ferric hydroxamate-binding lipoprotein (FhuD2) protein or polypeptide, capsular polysaccharide type 5, capsular polysaccharide type 8; or a combination, fragment and/or portion thereof. In some embodiments, the bacterial molecule is from Staphylococcus. In some embodiments, the bacterial molecule is from Staphylococcus aureus. [00109] In some embodiments, the antibody or the antigen binding fragment of the antibody is selected from Altastaph, Veronate, Aurexis (tefibazumab), pagibaximab (BSYX-Al lO), Aurograb, SAR279356 (F598), MEDI4893, Salvecin (AR-301, KBSA301), and 514G3 (XBiotech).

[00110] In some embodiments, the antibody or the antigen-binding fragment of the antibody comprises a variable domain and/or one or more CDRs from SEQ ID NOS: 14-23.

[00111] In another aspect, provided herein is a combination comprising an antibody or an antigen binding fragment of the antibody, and a compound of Formula (I)

Formula (I)

or pharmaceutically acceptable salt or solvate thereof, wherein:

n is 1, 2, 3, or 4.

[00112] In some embodiments, the antibacterial compound of Formula (I) has the structure of Formula (la)

Formula (la)

or pharmaceutically acceptable salt or solvate thereof, wherein:

X¹, X², X³, X⁴, and X⁵ are independently selected from N, CH, and CR⁴;

Y¹, Y², Y³, Y⁴, and Y⁵ are independently selected from N, CH, and CR⁴;

p is 0, 1, 2, 3, 4 or 5.

[00113] In some embodime structure of Formula (lb)

Formula (lb)

or pharmaceutically acceptable salt or solvate thereof, wherein:

C₇cycloalkyl;

[00114] In some embodi re of avasimibe

or pharmaceutically acceptable salt or solvate thereof.

[00115] In some embodiments, the antibody or an antigen binding fragment of the antibody and the compound of Formula (I) are formulated in a composition. In some embodiments, the antibody or an antigen binding fragment of the antibody and the compound of Formula (I) are formulated in separate compositions. In some embodiments, the antibody or an antigen binding fragment of the antibody is formulated for oral administration, intravenous administration or administration by nasogastric or orogastric intubation. In some embodiments, the compound of Formula (I) is formulated for oral administration, intravenous administration or administration by nasogastric or orogastric intubation. In some embodiments, the antibody or an antigen binding fragment of the antibody is formulated in a tablet, pill, gel-cap, or liquid. In some embodiments, the compound of Formula (I) is formulated in a tablet, pill, gel-cap, or liquid.

[00116] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a peptide or portion thereof from a bacteria selected from Staphylococcus, Bacillus, Enterococcus , Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, and Klebsiella. In some embodiments, the bacteria to which the antibody or the antigen-binding fragment of the antibody binds is drug-resistant. In some embodiments, the drug-resistant bacteria is resistant to methicillin. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is humanized.

[00117] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to an autolysin or fragment thereof. In some embodiments, the autolysin is from a bacteria selected from

[00118] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a bacterial autolysin N-acetylmuramoyl-L-alanine amidase catalytic domain or a fragment or portion thereof. In some embodiments, the bacterial autolysin N-acetylmuramoyl-L-alanine amidase catalytic domain is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

[00119] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a bacterial cell wall binding domain, or a fragment or portion thereof. In some embodiments, the bacterial cell wall binding domain is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

[00120] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a bacterial cell surface-associated antigen, or a fragment or portion thereof. In some embodiments, the bacterial cell surface -associated antigen is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

[00121] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a bacterial exotoxin, or a fragment or portion thereof. In some embodiments, the bacterial exotoxin is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

[00122] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a bacterial protease, or a fragment or portion thereof. In some embodiments, the bacterial protease is V8 protease, a member of the glutamyl endopeptidase I family of Staphylococcus aureus V8 strain (GluV8), or a fragment or portion thereof. In some embodiments, the bacterial protease is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia,

Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

[00123] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a bacterial leucocidin, or a fragment or portion thereof. In some embodiments, the bacterial leucocidin is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

[00124] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a bacterial adhesin, or a fragment or portion thereof. In some embodiments, the bacterial adhesin is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof. In some embodiments, the bacterial adhesin is a surface-bound adhesin that promotes host colonization.

[00125] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a cell surface adhesin that interacts with an extracellular matrix component (microbial surface component recognizing adhesive matrix molecules or MSCRAMMs), or a fragment or portion thereof.

[00126] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to lipoteichoic acid (LTA), or a fragment or portion thereof. In some embodiments, the antibody is pagibaximab

(BSYX-A110).

[00127] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to

Clumping Factor A (ClfA), or a fragment or portion thereof. In some embodiments, the antibody is tefibazumab. In some embodiments, the antibody is Veronate. [00128] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to ATP- binding cassette (ABC) transporter component GrfA, or a fragment or portion thereof. In some embodiments, the antibody is Aurograb.

[00129] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to poly-N- acetylated glucosamine (PNAG) , or a fragment or portion thereof. In some embodiments, the antibody is SAR279356 (F598).

[00130] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to alpha- toxin (AT), or a fragment or portion thereof. In some embodiments, the antibody is MEDI4893. In some embodiments, the antibody is AR-301.

[00131] In some embodiments, the antibody or the antigen-binding fragment of the antibody binds to a bacterial molecule selected from an amidase (Amd) protein or polypeptide, an iron-regulated surface determinant protein A (IsdA) protein or polypeptide, an iron-regulated surface determinant protein B (IsdB) protein or polypeptide, an iron-regulated surface determinant protein H (IsdH) protein or polypeptide, a Clumping Factor A (ClfA) protein or polypeptide, a Clumping Factor B (ClfB) protein or polypeptide, a Fibronectin Binding Protein A (FnbpA) protein or polypeptide, a Staphylococcus Complement Inhibitor (SCIN) protein or polypeptide, a Chemotaxis Inhibitory Protein of Staphylococcus aureus (CHIPS) protein or polypeptide, an alpha-Hemolysin (Hla) protein or polypeptide, an Extracellular Fibrinogen-binding (Efb) protein or polypeptide, S pro-toxin subunit from Staphylococcus (LukS-PV) protein or polypeptide, Ser-Asp dipeptide repeat G from (SdrG) protein or polypeptide, staphylococcal enteroxin B (SEB) protein or polypeptide, N-terminus of the candidal surface adhesin (rAls3p-N) protein or polypeptide, extracellular adherence protein (Eap) protein or polypeptide, Serine aspartate repeat containing protein D (SdrD) protein or polypeptide, Serine aspartate repeat containing protein E (SdrE) protein or polypeptide, staphylococcal antigen A (IsaA) protein or polypeptide, protein A or a polypeptide of protein A, panton-valentine leucocidin (PVL) protein or polypeptide, γ-hemolysin C (HlgC) protein or polypeptide, Ferric hydroxamate-binding lipoprotein (FhuD2) protein or polypeptide, capsular polysaccharide type 5, capsular polysaccharide type 8; or a combination, fragment and/or portion thereof. In some embodiments, the bacterial molecule is from Staphylococcus. In some embodiments, the bacterial molecule is from Staphylococcus aureus.

[00132] In some embodiments, the antibody or the antigen binding fragment of the antibody is selected from Altastaph, Veronate, Aurexis (tefibazumab), pagibaximab (BSYX-A110), Aurograb, SAR279356 (F598), MEDI4893, Salvecin (AR-301, KBSA301), and 514G3 (XBiotech).

[00133] In some embodiments, the antibody or the antigen-binding fragment of the antibody comprises a variable domain and/or one or more CDRs from SEQ ID NOS: 14-23.

[00134] Further provided is a method of treating a bacterial infection in a subject in need thereof, the method comprising administering to the subject the combination of the antibody or an antigen binding fragment of the antibody, and the compound of Formula (I). BRIEF DESCRIPTION OF THE DRAWINGS

[00135] The foregoing summary, as well as the following detailed description of the disclosure, will be better understood when read in conjunction with the appended figures. It should be understood, however, that the disclosure is not limited to the precise examples shown. It is emphasized that, according to common practice, the various features of the drawings are not to-scale. On the contrary, the dimensions of the various features are arbitrarily expanded or reduced for clarity. Included in the drawings are the following figures.

[00136] FIG. 1 shows the structure of avasimibe.

[00137] FIG. 2 shows inhibition of wild-type S. aureus and MRSA isolates with avasimibe (ASMB) concentration, as described in Example 1.

[00138] FIG. 3 shows inhibition of S. aureus with avasimibe without (medium control) or with additives associated with proposed mechanisms of avasimibe action. Additives THF, DHF and cholesterol each failed to rescue inhibition of S. aureus by avasimibe.

[00139] FIG. 4 shows the killing of S. aureus as measured in CFU/ml as a function of exposure time in hours, with different concentrations of avasimibe (4 uM, 8 uM, and 10 uM ASMB) or control DMSO, as described in Example 2.

[00140] FIG. 5 shows a synergistic effect on killing of S. aureus with a combination of avasimibe (ASMB) and kanamycin, as described in Example 3.

DETAILED DESCRIPTION OF THE INVENTION

[00141] Disclosed herein are antibacterial compounds, compositions, and combinations, useful for killing or otherwise inhibiting growth, replication and/or propagation of a bacteria. These antibacterial compounds are particularly useful for treating a subject infected with a bacteria having resistance to one or more other antibacterial compounds, such as polymyxin antibiotics or commonly used antibiotics such as beta-lactam antibiotics. Avasimibe is an exemplary antibacterial compound disclosed herein which is useful for the treatment of an infection caused by a drug-resistant bacteria. Exemplary combinations include avasimibe and an additional antibacterial agent, including, but without limitation, an antibiotic and/or an antibody that binds to a bacterial molecule. The antibody may bind to a Staphylococcus molecule, such as an autolysin, or portion thereof.

[00142] Before the present methods and compositions are described, it is to be understood that this disclosure is not limited to a particular method or composition described, and as such variations of the embodiments described may be apparent to one of skill in the art without deviating from this disclosure. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims. Examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g. amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric.

[00143] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range where either, neither or both limits are included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[00144] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, some potential and preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. It is understood that the present disclosure supersedes any disclosure of an incorporated publication to the extent there is a contradiction.

[00145] As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present invention. Any recited method can be carried out in the order of events recited or in any other order which is logically possible.

[00146] It must be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a bacteria" includes a plurality of such bacteria and reference to "the compound" includes reference to one or more compounds and derivatives or analogs thereof known to those skilled in the art, and so forth. As used herein, "about" refers to a numeric value, including, for example, whole numbers, fractions, and percentages, whether or not explicitly indicated. The term "about" generally refers to a range of numerical values (e.g., +/- 5-10% of the recited value) that one of ordinary skill in the art would consider equivalent to the recited value (e.g., having the same function or result). In some instances, the term "about" may include numerical values that are rounded to the nearest significant figure.

[00147] As used herein, the term "percent identity" when used herein to describe to an amino acid sequence or a nucleic acid sequence, relative to a reference sequence, can be determined using the formula described by Karlin and Altschul (Proc. Natl. Acad. Sci. USA 87: 2264-2268, 1990, modified as in Proc. Natl. Acad. Sci. USA 90:5873-5877, 1993). Such a formula is incorporated into the basic local alignment search tool (BLAST) programs of Altschul et al. (J. Mol. Biol. 215: 403-410, 1990). Percent identity of sequences can be determined using the most recent version of BLAST, as of the filing date of this application.

Antibacterial compounds

[00148] In one aspect, a compound is provided having antibacterial activity. Antibacterial activity includes killing bacteria, inhibiting or reducing growth, replication and/or propagation of bacteria, or a combination thereof, upon exposure of the bacteria to the antibacterial compound. The bacteria may be a causative agent of a disease in a subject, and the bacteria is exposed to the antibacterial compound by administration to the subject to exert the antibacterial activity within the subject. In other cases, the bacteria is present ex vivo and the antibacterial compound is exposed to the bacteria by bringing the bacteria and the antibacterial compound in sufficient proximity to exert an antibacterial effect. For instance, the antibacterial compound is applied to a surface comprising the bacteria. e a structure of Formula (I):

Formula (I)

or pharmaceutically acceptable salt or solvate thereof, wherein:

X and Y are independently selected from -0-, -S-, and (-CR⁸R⁹-)_n; wherein each R⁸ and R⁹ are independently selected from H, -F, -CI, -Br, -I, -OR⁵, -C(0)R⁵, substituted or unsubstituted Ci-C₇alkyl; substituted or unsubstituted C₃-C₇cycloalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; n is 1, 2, 3, or 4.

[00149] The antibacterial com a):

Formula (la)

or pharmaceutically acceptable salt or solvate thereof, wherein:

X¹, X², X³, X⁴, and X⁵ are independently selected from N, CH, and CR⁴;

Y¹, Y², Y³, Y⁴, and Y⁵ are independently selected from N, CH, and CR⁴;

p is 0, 1, 2, 3, 4 or 5.

[00150] The antibacterial compound of Formula (la) may have the structure of Formula (lb):

Formula (lb)

or pharmaceutically acceptable salt or solvate thereof, wherein:

C₇cycloalkyl;

[00151] The antibacterial compound of Formula (lb) may have the structure of avasimibe

or pharmaceutically acceptable salt or solvate thereof. [00152] The antibacterial compounds disclosed herein, including the compounds of Formula (I), (la) or (lb), may be prepared by methods known in the field of synthetic chemistry. A compound of Formula (I), (la) or (lb), or a pharmaceutically acceptable salt, solvate or prodrug thereof, may be formulated with a

pharmaceutically acceptable excipient in a pharmaceutical composition. The pharmaceutical composition may be used in the treatment or prevention of a bacterial infection.

[00153] In the preceding description of antibacterial compounds suitable for use in the methods described herein, definitions of referred-to standard chemistry terms may be found in reference works (if not otherwise defined herein), including Carey and Sundberg "Advanced Organic Chemistry 4th Ed." Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology, within the ordinary skill of the art are employed. Unless specific definitions are provided, the nomenclature employed in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those known in the art. Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients.

[00154] Bacteria

[00155] Antibacterial compounds provided herein may have antibacterial activity for a Gram-positive and/or Gram-negative bacteria. Antibacterial compounds include those having Formula (I), (la) and (lb), such as avasimibe. In some cases, the antibacterial compound is active against both wild-type and drug-resistant bacteria. Non-limiting examples of Gram-positive bacteria include those having genus Staphylococcus, Bacillus, Enter ococcus, Streptococcus, and Clostridium. In some embodiments, an antibacterial compound provided herein has antibacterial activity for Staphylococcus . In some cases, the Staphylococcus is wild-type. In some cases, the Staphylococcus is drug-resistant, or multi-drug resistant Staphylococcus aureus (MRS A). The Gram-positive bacteria may be one or more of Staphylococcus aureus, Staphylococcus epidermidis, Bacillus subtilis, Enterococcus faecium, Streptococcus pneumonia, Streptococcus pyogenes, and Clostridium difficile. Non-limiting examples of Gram-negative bacteria include those having genus Pseudomonas, Escherichia, Haemophilus, Acinetobacter, and Klebsiella. The Gram-negative bacteria may be one or more of Pseudomonas aeruginosa, Escherichia coli, Haemophilus influenzae, Acinetobacter baumannii, and

Klebsiella pneumonia.

[00156] Antibacterial compounds provided herein may have antibacterial activity for a bacteria having drug resistance. In some embodiments, a bacteria having drug resistance (drug-resistant bacteria) is a bacteria that after treatment with the drug is not killed, growth is not inhibited, it is able to reproduce, or any combination thereof. In some embodiments, a bacteria having drug resistance (drug-resistant bacteria) is a population of bacteria, where at least a percentage of the bacteria are not killed, growth is not inhibited, and/or reproduction of the bacteria is not inhibited after treatment with the drug. Exemplary percentages include at least about 10%, 20%, 30%, 40%, or 50%. In some cases, a drug-resistant bacteria is resistant to a drug selected from one or more of penicillin, methicillin, oxacillin, nafcillin, ampicillin, amoxicillin, carbenicillin, vancomycin, erythromycin, doxycycline, tetracycline, linezolid, clindamycin, and ceftriazone.

[00157] Antibacterial compounds provided herein may have antibacterial activity for one or more of:

Staphylococcus aureus NCTC8325, Methicillin-resistant Staphylococcus aureus USA300 (ATCC BAA- 1717), Methicillin-resistant Staphylococcus aureus USA200 (ATCC BAA-1720), Bacillus subtilis strain 168, Pseudomonas aeruginosa strain PAO l, Escherichia coli K-12 MG1655, Staphylococcus aureus Smith ATCC 13709, Methicillin-resistant Staphylococcus aureus USA100 NRS690, Methicillin-resistant

Staphylococcus aureus USA 100 NRS710, Methicillin-resistant Staphylococcus aureus USA200 NRS651, Methicillin-resistant Staphylococcus aureus USA300 NRS659, Methicillin-resistant Staphylococcus aureus USA300 NRS687, Methicillin-resistant Staphylococcus aureus USA300 NRS702, Methicillin-resistant Staphylococcus aureus USA300 NRS739, Methicillin-resistant Staphylococcus aureus USA400 NRS 123, Methicillin-resistant Staphylococcus aureus USA600 NRS22, Glycopeptide-intermediate Staphylococcus aureus NRS26, Glycopeptide-intermediate Staphylococcus aureus NRS29, Staphylococcus epidermidis RP62A ATCC 35984, vancomycin-resistant Enterococcus faecium strain 752, vancomycin-resistant

Enterococcus faecalis strain 848, Streptococcus pneumonia ATCC 49619, Streptococcus pyogenes

ATCC 19615, Clostridium difficile strain VA1 1, Haemophilus influenzae ATCC 49247, Ampicillin/

Erythromycin resistant Haemophilus influenzae H539, Acinetobacter baumannii ATCC 19606, and

Klebsiella pneumonia 82-3632A. In some cases, an antibacterial compound described herein is useful for killing or inhibiting a bacteria which is not listed herein, yet has developed resistance to a drug by horizontal gene transfer or other means.

Methods of use

[00158] Antibacterial compounds disclosed herein are useful for treating or preventing one or more diseases, conditions, and/or symptoms of a disease, caused by infection of a subject with a bacteria. Treatment and prevention includes exerting an antibacterial effect on the bacteria by: killing the bacteria; and/or inhibiting and/or reducing growth, replication and/or propagation of the bacteria after administration of the antibacterial compound to the subject. The antibacterial compound may be formulated for oral or intravenous injection and can be administered in an outpatient or inpatient setting, such as in a hospital. Antibacterial compounds include avasimibe, and compounds having Formula (I), (la) or (lb). Furthermore, antibacterial compounds disclosed herein may exert an antibacterial effect on a bacteria present outside of a subject, for example, on a surface of an object or an outer surface of the subject's body. In such cases, methods are provided for treated a surface with an antibacterial compound disclosed herein. Exemplary methods include disinfecting surfaces of surgical tools, hands, bathroom surfaces, and any surface that is amenable to disinfection.

[00159] Methods involve contacting bacteria with an effective amount of an antibacterial compound, such as one having Formula (I), (la) or (lb). Further methods include contacting the bacteria with a combination of the antibacterial compound and an additional antibacterial agent, such as an antibody that binds to a bacterial molecule, or portion thereof. The contacting may be carried out in vitro (e.g. , in biochemical and/or cellular assays), in vivo in a non-human animal, in vivo in mammals, including humans and/or ex vivo (e.g. , for sterilization purposes). Contacting may involve bringing a bacterial cell and an antibacterial compound into sufficient proximity such that the antibacterial compound can exert an effect on the bacterial cell. The antibacterial may be transported to the location of the bacterial cell, or the antibacterial may be situated in a location to which the bacterial cell travels or is brought into contact. Contacting includes physical interaction between the antibacterial compound and a bacterial cell, as well as interactions that do not require physical interaction.

[00160] As used herein, a "subject" means an animal, such as a mammal, including humans, other higher primates, lower primates, and animals of veterinary importance, such as dogs, cats, horses, sheep, goats, and cattle and the like. The subject may have a bacterial infection, may be at risk for developing a bacterial infection, or may be at greater risk than the general population for exposure to infectious bacteria. In some cases, the subject is immunocompromised. In some cases, the subject has Human Immunodeficiency Virus (HIV) or acquired immune deficiency syndrome (AIDS).

[00161] As used herein, "bacterial infection" refers to an infection caused by a species or strain of bacteria for which the methods disclosed herein are appropriate. Non-limiting examples of such bacteria include

Staphylococcus aureus (methicillin-susceptible and -resistant strains; vancomycin-susceptible, -intermediate, - hetero-intermediate and -resistant strains), Staphylococcus pyogenes, Staphylococcus agalactiae,

Streptococcus anginosus grp. (including S. anginosus, S. intermedius, and S. constellatus), Streptococcus dysgalactiae (including S. dysgalactiae subsp. equisimilis), Streptococcus pneumoniae, Streptococci species, including Streptococci Group A species, Streptococci Group B species, Streptococci Group C species, and Streptococci Group D species, Enterococci species, Enterococcus faecalis (vancomycin-susceptible and - resistant strains), Enterococcus faecium (vancomycin-susceptible and -resistant strains), Staphylococcus epidermidis (methicillin-susceptible and -resistant strains), Staphylococcus haemolyticus , Bacillus anthracis, and Clostridium difficile (both vegetative form and spores).

[00162] In certain embodiments, the compound of Formula (I), (la), or (lb) is administered to treat infection of the subject with S. aureus. In certain embodiments, the compound of Formula (I), (la), or (lb) is administered to prevent infection of the subject with S. aureus. In some cases, the compound of Formula (I) is administered prior to, during, and/or within 1 year of the subject undergoing a medical procedure. As a non-limiting example, the medical procedure is surgery. Surgery includes the subject receiving an implant, such as an orthopedic implant. Orthopedic implants include a joint prosthesis, graft or synthetic implant. For instance, in some cases the compound of Formula (I), (la), or (lb) is administered to treat a bacterial infection in a bone of the subject and/or within a 1 inch region of the bone of the subject. Such cases may occur when the subject has osteomyelitis and/or a periprosthetic infection.

[00163] Administration frequencies for a pharmaceutical composition of an antibacterial compound having Formula (I), (la) or (lb) may vary based on the method being practiced, the physical characteristics of the subject, the severity of the subject's symptoms, the form of the infection, the identity of the bacteria, and the formulation and the means used to administer the antibacterial compound. Administration frequencies may include 6, 5, 4, 3, 2 or once daily, every other day, every third day, every fourth day, every fifth day, every sixth day, once weekly, every eight days, every nine days, every ten days, bi-weekly, monthly and bi-monthly. In certain aspects, the pharmaceutical composition is administered once daily. The duration of treatment will be based on the condition being treated and may be determined by the attending physician. Under some conditions, treatment is continued for a number of days, weeks, or months. Under other conditions, complete treatment is achieve through administering one, two or three dose of the pharmaceutical composition over the entire course of treatment. In certain aspects, complete treatment can be achieved using a single dose of the pharmaceutical composition.

[00164] Each of the methods may also be practiced by administering an additional therapeutic agent to the subject. Such additional therapeutic agents may be included in a pharmaceutical formulation comprising a compound of Formula (I), (la) or (lb), or the additional therapeutic agent may be administered separately, whether concurrently or sequentially, in either order. A wide range of additional therapeutic agents, such as antibiotics, can be used in combination with the compounds, compositions and methods described herein. Antibiotics used as an additional therapeutic agent may act by interfering with cell wall synthesis, plasma membrane integrity, nucleic acid synthesis, ribosomal function, folate synthesis, etc. A non-limiting list of antibiotics includes: a polymyxin (e.g., colistin), a polymyxin derived antibacterial agent, fusidic acid, a fusidic acid derived antibacterial agent, trimethoprim, a trimethoprim derived antibacterial agent, sulfadiazine, a sulfadiazine derived antibacterial agent, sulfamethoxazole, a sulfamethoxazole derived antibacterial agent, a penicillin, a penicillin derived antibacterial agent, a monobactam, a monobactam derived antibacterial agent, a penam, a penem derived antibacterial agent, a clavam, a clavem derived antibacterial agent, a carbopenam, a carbopenem derived antibacterial agent, a cepham, a cephem derived antibacterial agent, an oxacepham, an oxacephem derived antibacterial agent, a carbocepham, a carbocephem derived antibacterial agent, a cephalosporin, cephalosporin derived antibacterial agent, tetracycline, a tetracycline derived antibacterial agent, glycylcycline, a glycylcycline derived antibacterial agent, minocycline, a minocycline derived antibacterial agent, sancycline, a sancycline derived antibacterial agent, methacycline, a methacycline derived antibacterial agent, an oxazolidinone antibacterial agent, an aminoglycoside antibacterial agent, an additional glycopeptide or lipoglycopeptide, a quinolone antibacterial agent, daptomycin, a daptomycin derived antibacterial agent, rifamycin, a rifamycin derived antibacterial agent, rifampin, a rifampin derived antibacterial agent, rifalazil, a rifalazil derived antibacterial agent, rifabutin, a rifabutin derived antibacterial agent, rifapentin, a rifapentin derived antibacterial agent, rifaximin and a rifaximin derived antibacterial agent. In some cases, an additional therapeutic agent is an additional antibacterial compound. As a non-limiting example, the additional antibacterial compound is an aminoglycoside. Aminoglycosides include, without limitation, kanamycin, amikacin, apramycin, arbekacin, astromicin, bekanamycin, capreomycin, dibekacin, dihydrostreptomycin, elsamitrucin, fosfomycin, tobramycin, g418, gentamicin, hygromycin b, isepamicin, kanamycin, kasugamycin, legonmycin, lividomycin, micronomicin, neamine, neomycin, netilmicin, nourseothricin, paromomycin, plazomicin, ribostamycin, sisomicin, streptoduocin, streptomycin, tobramycin, totomycin, and verdamicin. In some cases, the additional therapeutic agent is an antibody, for example, an antibody that binds to a bacteria, as described herein. [00165] Some methods comprise administering to the subject the compound of Formula (I), (la), or (lb) and an antibody or an antigen-binding fragment of the antibody. In some cases, the antibody or the antigen-binding fragment of the antibody is administered with the antibacterial compound of Formula (I), (la), or (lb). In some cases, the antibody or the antigen-binding fragment of the antibody is administered separately from the antibacterial compound of Formula (I), (la), or (lb). In some cases, the antibody or the antigen-binding fragment of the antibody is administered in a separate composition from the antibacterial compound of Formula (I), (la), or (lb). In some cases, the antibody or the antigen-binding fragment of the antibody is administered as a vaccine to prevent the bacterial infection. In some cases, the subject is an individual who has a greater risk than the general population for developing the bacterial infection. In some cases, the antibody or the antigen-binding fragment of the antibody is administered during passive immunization. In some cases, the antibody or the antigen-binding fragment of the antibody is administered for the treatment of active bacterial infection. In some cases, the antibody is administered during active immunization.

[00166] Antibodies described herein include full-length antibodies and any antibody fragment which may bind to an antigen, i.e., an antigen-binding fragment. As such, reference to an antibody includes an antibody fragment of the antibody. In some cases, the antibody promotes lysis of the bacteria. In some cases, the antibody binds to a molecule from a bacteria selected from Staphylococcus, Bacillus, Enterococcus,

Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, and Klebsiella. In some cases, the bacteria is drug-resistant. In some cases, the bacteria is methicillin resistant. In some cases, the antibody is a monoclonal antibody. In some cases, the antibody is humanized.

[00167] In some embodiments, an antibody for use in a combination herein (e.g., combination composition and/or combination method of use with a compound of Formula (I), (la), or (lb)) binds to an autolysin or fragment thereof. In some cases, the autolysin is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, and Klebsiella. In some cases, the bacteria is Stapylococcus. In some cases, the antibody at least partially or wholly binds to the glucosaminidase subunit of the autolysin, or a fragment of the glucosaminidase subunit. In some cases, the glucosaminidase comprises the sequence of SEQ ID NO: 1, as show in Table 1.. In some cases, the antibody binds to an epitope at least partially positioned within the glucosaminidase R3 domain. In some cases, the glucosaminidase is a Staphylococcus aureus glucosaminidase. In some cases, the antibody binds to an epitope within the glucosaminidase catalytic domain. In some cases, the antibody inhibits activity of the glucosaminidase. In some cases, the antibody comprises a variable domain sequence at least 80%, 85%, 90%, 95%, or 99% identical to a sequence selected from SEQ ID NO: 2-23, as show in Table 1.. In some cases, the antibody comprises one or more CDRs selected from SEQ ID NOS: 2-23. In some cases, the antibody comprises the sequences of amino acid residues 31-35, 50-66, and 99-1 10 of SEQ ID NO: 6 and/or the sequence of amino acid residues 24-31, 50-56, and 89-95 of SEQ ID NO: 1 1.

[00168] In some embodiments, an antibody for use in a combination herein (e.g., combination composition and/or combination method of use with a compound of Formula (I), (la), or (lb)) binds to a bacterial autolysin N-acetylmuramoyl-L-alanine amidase catalytic domain or a fragment or portion thereof. In some cases, the bacterial autolysin N-acetylmuramoyl-L-alanine amidase catalytic domain is from a bacteria selected from

Staphylococcus, Bacillus, Enter ococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia,

Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

[00169] In some embodiments, an antibody for use in a combination herein (e.g., combination composition and/or combination method of use with a compound of Formula (I), (la), or (lb)) binds to a bacterial cell wall binding domain, or a fragment or portion thereof. In some cases, the bacterial cell wall binding domain is from a bacteria selected from Staphylococcus, Bacillus, Enter ococcus, Streptococcus, Clostridium,

Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

[00170] In some embodiments, an antibody for use in a combination herein (e.g., combination composition and/or combination method of use with a compound of Formula (I), (la), or (lb)) binds to a bacterial cell surface-associated antigen, or a fragment or portion thereof. In some cases, the bacterial cell surface- associated antigen is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

[00171] In some embodiments, an antibody for use in a combination herein (e.g., combination composition and/or combination method of use with a compound of Formula (I), (la), or (lb)) binds to a bacterial exotoxin, or a fragment or portion thereof. In some cases, the bacterial exotoxin is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia,

Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

[00172] In some embodiments, an antibody for use in a combination herein (e.g., combination composition and/or combination method of use with a compound of Formula (I), (la), or (lb)) binds to a bacterial protease, or a fragment or portion thereof. In some cases, the bacterial protease is V8 protease, a member of the glutamyl endopeptidase I family of Staphylococcus aureus V8 strain (GluV8), or a fragment or portion thereof. In some cases, the bacterial protease is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

[00173] In some embodiments, an antibody for use in a combination herein (e.g., combination composition and/or combination method of use with a compound of Formula (I), (la), or (lb)) binds to a bacterial leucocidin, or a fragment or portion thereof. In some cases, the bacterial leucocidin is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

[00174] In some embodiments, an antibody for use in a combination herein (e.g., combination composition and/or combination method of use with a compound of Formula (I), (la), or (lb)) binds to a bacterial adhesin, or a fragment or portion thereof. In some cases, the bacterial adhesin is from a bacteria selected from

Haemophilus, Acinetobacter, Klebsiella, and a combination thereof. In some cases, the bacterial adhesin is a surface-bound adhesin that promotes host colonization. [00175] In some embodiments, an antibody for use in a combination herein (e.g., combination composition and/or combination method of use with a compound of Formula (I), (la), or (lb)) binds to a cell surface adhesin that interacts with an extracellular matrix component (microbial surface component recognizing adhesive matrix molecules or MSCRAMMs), or a fragment or portion thereof.

[00176] In some embodiments, an antibody for use in a combination herein (e.g., combination composition and/or combination method of use with a compound of Formula (I), (la), or (lb)) binds to lipoteichoic acid (LTA), or a fragment or portion thereof. In some cases, the antibody is pagibaximab (BSYX-A1 10).

[00177] In some embodiments, an antibody for use in a combination herein (e.g., combination composition and/or combination method of use with a compound of Formula (I), (la), or (lb)) binds to Clumping Factor A (ClfA), or a fragment or portion thereof. In some cases, the antibody is tefibazumab. In some cases, the antibody is Veronate.

[00178] In some embodiments, an antibody for use in a combination herein (e.g., combination composition and/or combination method of use with a compound of Formula (I), (la), or (lb)) binds to ATP-binding cassette (ABC) transporter component GrfA, or a fragment or portion thereof. In some cases, the antibody is Aurograb.

[00179] In some embodiments, an antibody for use in a combination herein (e.g., combination composition and/or combination method of use with a compound of Formula (I), (la), or (lb)) binds to poly-N-acetylated glucosamine (PNAG) , or a fragment or portion thereof. In some cases, the antibody is SAR279356 (F598).

[00180] In some embodiments, an antibody for use in a combination herein (e.g., combination composition and/or combination method of use with a compound of Formula (I), (la), or (lb)) binds to alpha-toxin (AT), or a fragment or portion thereof. In some cases, the antibody is MEDI4893. In some cases, the antibody is AR- 301.

[00181] In some embodiments, an antibody for use in a combination herein (e.g., combination composition and/or combination method of use with a compound of Formula (I), (la), or (lb)) binds to a bacterial molecule selected from an amidase (Amd) protein or polypeptide, an iron-regulated surface determinant protein A (IsdA) protein or polypeptide, an iron-regulated surface determinant protein B (IsdB) protein or polypeptide, an iron-regulated surface determinant protein H (IsdH) protein or polypeptide, a Clumping Factor A (ClfA) protein or polypeptide, a Clumping Factor B (ClfB) protein or polypeptide, a Fibronectin Binding Protein A (FnbpA) protein or polypeptide, a Staphylococcus Complement Inhibitor (SCIN) protein or polypeptide, a Chemotaxis Inhibitory Protein of Staphylococcus aureus (CHIPS) protein or polypeptide, an alpha-Hemolysin (Hla) protein or polypeptide, an Extracellular Fibrinogen-binding (Efb) protein or polypeptide, S pro-toxin subunit from Staphylococcus (LukS-PV) protein or polypeptide, Ser-Asp dipeptide repeat G from (SdrG) protein or polypeptide, staphylococcal enteroxin B (SEB) protein or polypeptide, N-terminus of the candidal surface adhesin (rAls3p-N) protein or polypeptide, extracellular adherence protein (Eap) protein or polypeptide, Serine aspartate repeat containing protein D (SdrD) protein or polypeptide, Serine aspartate repeat containing protein E (SdrE) protein or polypeptide, staphylococcal antigen A (IsaA) protein or polypeptide, protein A or a polypeptide of protein A, panton-valentine leucocidin (PVL) protein or polypeptide, γ-hemolysin C (HlgC) protein or polypeptide, Ferric hydroxamate -binding lipoprotein (FhuD2) protein or polypeptide, capsular polysaccharide type 5, capsular polysaccharide type 8; or a combination, fragment and/or portion thereof. In some cases, the bacterial molecule is from Staphylococcus . In some cases, the bacterial molecule is from Staphylococcus aureus.

[00182] In some embodiments, an antibody for use in a combination herein (e.g., combination composition and/or combination method of use with a compound of Formula (I), (la), or (lb)) is selected from Altastaph, Veronate, Aurexis (tefibazumab), pagibaximab (BSYX-A110), Aurograb, SAR279356 (F598), MEDI4893, Salvecin (AR-301, KBSA301), and 514G3 (XBiotech).

[00183] Dosing and treatment regimens

[00184] A method for treating any of the diseases or conditions described herein in a subject in need of such treatment, involves administration of pharmaceutical compositions that include at least one compound of Formula (I), (la) or (lb) or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said subject. In another embodiment, the compounds of Formula (I), (la) or (lb) are used in the preparation of medicaments for treating a bacterial infection. Pharmaceutical compositions as used herein include compositions comprising a compound of Formula (I), (la), or (lb); and compositions comprising a combination of a compound of Formula (I), (la), or (lb) and an additional therapeutic agent. Additional therapeutic agents include antibacterial compounds and antibodies, including, but limited to the compounds and antibodies provided herein. For example, the antibody may bind to a bacterial autolysin, a bacterial glucosaminidase (e.g., from S. aureus), a bacterial cell wall binding domain, a bacterial cell surface-associated antigen, a bacterial exotoxin, a bacterial protease, a bacterial leucocidin, a bacterial adhesin, a MSCRAMM, lipoteichoic acid, Clumping Factor A, ABC transporter component GrfA, PNAG, alpha-toxin, an amidase (Amd), an iron-regulated surface determinant protein A (IsdA), an iron-regulated surface determinant protein B (IsdB), an iron- regulated surface determinant protein H (IsdH), a Clumping Factor B (ClfB), a Fibronectin Binding Protein A (FnbpA), a Staphylococcus Complement Inhibitor (SCIN), a Chemotaxis Inhibitory Protein of Staphylococcus aureus (CHIPS), an alpha-Hemolysin (Hla), an Extracellular Fibrinogen-binding (Efb), S pro-toxin subunit from Staphylococcus (LukS-PV), Ser-Asp dipeptide repeat G from (SdrG), staphylococcal enteroxin B (SEB), N-terminus of the candidal surface adhesin (rAls3p-N), extracellular adherence protein (Eap), Serine aspartate repeat containing protein D (SdrD), Serine aspartate repeat containing protein E (SdrE), staphylococcal antigen A (IsaA), protein A or a polypeptide of protein A, panton-valentine leucocidin (PVL), γ-hemolysin C (HlgC), Ferric hydroxamate -binding lipoprotein (FhuD2), capsular polysaccharide type 5, capsular polysaccharide type 8; or a combination, fragment and/or portion thereof. In some cases, the antibody comprises a sequence from SEQ ID NOS: 2-23. In some cases, the antibody comprises a CDR from any of SEQ ID NOS: 2-23.

[00185] In certain embodiments, the compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician.

Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation clinical trial. In some cases, an antibody is administered prior to a patient suffering from the disease or condition, and a compound of Formula (I), (la), or (lb) is administered during the disease or condition. In some cases, a combination of the antibody and the compound of Formula (I), (la), or (lb) is administered prior to, during, and/or after the disease or condition. Diseases and conditions include those resulting from bacterial infection.

[00186] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose." In this use, the precise amounts also depend on the patient's state of health, weight, and the like. When used in a patient, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound of Formula (I), (la) or (lb) in order to prevent a return of the symptoms of the disease or condition.

[00187] In certain embodiments wherein the patient's condition does not improve, upon the doctor's discretion the administration of the compound of Formula (I), (la) or (lb) is administered chronically, that is, for an extended period of time, including throughout the duration of the patient's life in order to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.

[00188] In certain embodiments wherein a patient's status does improve, the dose of drug being administered may be temporarily reduced or temporarily suspended for a certain length of time (i.e., a "drug holiday"). In specific embodiments, the length of the drug holiday is between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. The dose reduction during a drug holiday is, by way of example only, by 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%, and 100%.

[00189] In certain embodiments the dose of drug being administered may be temporarily reduced or temporarily suspended for a certain length of time (i.e., a "drug diversion"). In specific embodiments, the length of the drug diversion is between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. The dose reduction during a drug diversion is, by way of example only, by 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%, and 100%. After a suitable length of time, the normal dosing schedule is optionally reinstated. [00190] In some embodiments, once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, however, the patient requires intermittent treatment on a long-term basis upon any recurrence of symptoms.

[00191] The amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but can nevertheless be determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated. In general, however, doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day. In one aspect, doses employed for adult human treatment are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.

[00192] In some embodiments, as a patient is started on a regimen of an antibacterial compound, the patient is also weaned off (e.g., step-wise decrease in dose) a second treatment regimen.

[00193] In one embodiment, the daily dosages appropriate for a compound of Formula (I), (la) or (lb) described herein are from about 0.01 to about 10 mg/kg per body weight. In specific embodiments, an indicated daily dosage in a large mammal, including, but not limited to, humans, is in the range from about 0.5 mg to about 1000 mg, conveniently administered in divided doses, including, but not limited to, up to four times a day. In one embodiment, the daily dosage is administered in extended release form. In certain embodiments, suitable unit dosage forms for oral administration comprise from about 1 to 500 mg active ingredient. In other embodiments, the daily dosage or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime. In various embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[00194] Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD₅₀ and the ED₅₀. The dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD₅₀ and ED₅₀. In certain embodiments, the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and/or the therapeutically effective unit dosage amount for use in mammals, including humans. In some embodiments, the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED₅₀ with minimal toxicity. In certain embodiments, the daily dosage range and/or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.

Pharmaceutical compositions and formulations

[00195] Disclosed herein are antibacterial compounds having Formula (I), (la) or (lb), formulated into pharmaceutical compositions. The pharmaceutical composition may comprise avasimibe. The

pharmaceutical composition may comprise an antibody. The pharmaceutical composition may comprise a combination of the antibody and the compound having Formula (I), (la), or (lb). For example, the antibody may bind to a bacterial autolysin, a bacterial glucosaminidase (e.g., from S. aureus), a bacterial cell wall binding domain, a bacterial cell surface -associated antigen, a bacterial exotoxin, a bacterial protease, a bacterial leucocidin, a bacterial adhesin, a MSCRAMM, lipoteichoic acid, Clumping Factor A, ABC transporter component GrfA, PNAG, alpha-toxin, an amidase (Amd), an iron-regulated surface determinant protein A (IsdA), an iron-regulated surface determinant protein B (IsdB), an iron-regulated surface determinant protein H (IsdH), a Clumping Factor B (ClfB), a Fibronectin Binding Protein A (FnbpA), a Staphylococcus Complement Inhibitor (SCIN), a Chemotaxis Inhibitory Protein of Staphylococcus aureus (CHIPS), an alpha-Hemolysin (Hla), an Extracellular Fibrinogen-binding (Efb), S pro-toxin subunit from Staphylococcus (LukS-PV), Ser-Asp dipeptide repeat G from (SdrG), staphylococcal enteroxin B (SEB), N- terminus of the candidal surface adhesin (rAls3p-N), extracellular adherence protein (Eap), Serine aspartate repeat containing protein D (SdrD), Serine aspartate repeat containing protein E (SdrE), staphylococcal antigen A (IsaA), protein A or a polypeptide of protein A, panton-valentine leucocidin (PVL), γ-hemolysin C (HlgC), Ferric hydroxamate -binding lipoprotein (FhuD2), capsular polysaccharide type 5, capsular polysaccharide type 8; or a combination, fragment and/or portion thereof. In some cases, the antibody comprises a sequence from SEQ ID NOS: 2-23. In some cases, the antibody comprises a CDR from any of SEQ ID NOS: 2-23.

[00196] Pharmaceutical compositions are formulated in a conventional manner using one or more

pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed.

(Lippincott Williams & Wilkins, 1999), herein incorporated by reference for such disclosure.

[00197] Provided herein are pharmaceutical compositions that include a compound of Formula (I), (la) or (lb), and at least one pharmaceutically acceptable inactive ingredient. Optionally, the compositions include an antibody or other therapeutic agent as discussed herein, e.g., an antibiotic or other antibacterial compound. In some embodiments, the compounds described herein are administered as pharmaceutical compositions in which compounds of Formula (I), (la) or (lb), are mixed with other active ingredients, as in combination therapy. In other embodiments, the pharmaceutical compositions include other medicinal or pharmaceutical agents, carriers, adjuvants, preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, and/or buffers. In yet other embodiments, the pharmaceutical compositions include other therapeutically valuable substances.

[00198] A pharmaceutical composition, as used herein, refers to a mixture of a compound of Formula (I), (la) or (lb), with other chemical components (i.e. pharmaceutically acceptable inactive ingredients), such as carriers, excipients, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, or one or more combination thereof. Optionally, the compositions include an antibody or other therapeutic agent as discussed herein, e.g., an antibiotic or other antibacterial compound. The pharmaceutical composition facilitates administration of the compound to an organism. In practicing the methods of treatment or use provided herein, therapeutically effective amounts of compounds described herein are administered in a pharmaceutical composition to a mammal having a disease, disorder, or condition to be treated. In some embodiments, the mammal is a human. A therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. The compounds can be used singly or in combination with one or more therapeutic agents as components of mixtures.

[00199] The pharmaceutical formulations described herein are administered to a subject by appropriate administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, or transdermal administration routes. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[00200] Pharmaceutical compositions including a compound of Formula (I), (la) or (lb) are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes. Optionally, the compositions include an antibody or other therapeutic agent as discussed herein, e.g., an antibiotic or other antibacterial compound.

[00201] The pharmaceutical compositions will include at least one compound of Formula (I), (la) or (lb) as an active ingredient in free-acid or free-base form, or in a pharmaceutically acceptable salt form. In addition, the methods and pharmaceutical compositions described herein include the use of N-oxides (if appropriate), crystalline forms, amorphous phases, as well as active metabolites of these compounds having the same type of activity. In some embodiments, compounds of Formula (I), (la) or (lb) exist in unsolvated form or in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds of Formula (I), (la) or (lb) are also considered to be disclosed herein.

[00202] In some embodiments, the compounds of Formula (I), (la) or (lb) exist as tautomers. All tautomers are included within the scope of the compounds presented herein. As such, it is to be understood that a compound of the Formula (I), (la) or (lb) or a salt thereof may exhibit the phenomenon of tautomerism whereby two chemical compounds that are capable of facile interconversion by exchanging a hydrogen atom between two atoms, to either of which it forms a covalent bond. Since the tautomeric compounds exist in mobile equilibrium with each other they may be regarded as different isomeric forms of the same compound. It is to be understood that the formulae drawings within this specification can represent only one of the possible tautomeric forms. However, it is also to be understood that the present disclosure encompasses any tautomeric form, and is not to be limited merely to any one tautomeric form utilized within the formulae drawings. The formulae drawings within this specification can represent only one of the possible tautomeric forms and it is to be understood that the specification encompasses all possible tautomeric forms of the compounds drawn not just those forms which it has been convenient to show graphically herein.

[00203] In some embodiments, compounds of Formula (I), (la) or (lb) exist as enantiomers, diastereomers, or other steroisomeric forms. The compounds disclosed herein include all enantiomeric, diastereomeric, and epimeric forms as well as mixtures thereof.

[00204] In some embodiments, compounds described herein may be prepared as prodrugs. A "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in

pharmaceutical compositions over the parent drug. An example, without limitation, of a prodrug would be a compound described herein, which is administered as an ester (the "prodrug") to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial. A further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.

[00205] Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound of (I) as set forth herein are included within the scope of the claims. Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound of Formula (I), (la) or (lb) as set forth herein are included within the scope of the claims. In some cases, some of the compounds described herein may be a prodrug for another derivative or active compound. In some embodiments described herein, hydrazones are metabolized in vivo to produce a compound of Formula (I), (la) or (lb). [00206] In certain embodiments, compositions provided herein include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

[00207] In some embodiments, formulations described herein benefit from antioxidants, metal chelating agents, thiol containing compounds and other general stabilizing agents. Examples of such stabilizing agents, include, but are not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1% to about 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate 80, (g) 0.001% to about 0.05% w/v. polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (1) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.

[00208] The pharmaceutical compositions described herein, which include a compound of Formula (I), (la) or (lb) are formulated into any suitable dosage form, including but not limited to, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, solid oral dosage forms, aerosols, controlled release formulations, fast melt formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations.

[00209] Certain systemically administered compositions

[00210] In one aspect, (i) a compound of Formula (I), (la) or (lb); (ii) an antibody or other therapeutic agent as discussed herein, e.g., an antibiotic or other antibacterial compound; or a combination of (i) and (ii) is formulated into a pharmaceutical composition suitable for intramuscular, subcutaneous, or intravenous injection. In one aspect, formulations suitable for intramuscular, subcutaneous, or intravenous injection include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propyleneglycol, polyethylene-glycol, glycerol, cremophor and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can 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 dispersions, and by the use of surfactants. In some embodiments, formulations suitable for subcutaneous injection also contain additives such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the growth of microorganisms can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. In some cases it is desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, such as aluminum monostearate and gelatin.

[00211] For intravenous injections or drips or infusions, compounds described herein are formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. For other parenteral injections, appropriate formulations include aqueous or nonaqueous solutions, preferably with physiologically compatible buffers or excipients. Such excipients are known.

[00212] Parenteral injections may involve bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The pharmaceutical composition described herein may be in a form suitable for parenteral injection as a sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. In one aspect, the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[00213] For administration by inhalation, a compound of Formula (I), (la) or (lb) and/or an additional therapeutic agent, is formulated for use as an aerosol, a mist or a powder. Pharmaceutical compositions described herein are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane,

trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, such as, by way of example only, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound described herein and a suitable powder base such as lactose or starch.

[00214] Representative intranasal formulations are described in, for example, U.S. Pat. Nos. 4,476, 1 16, 5, 1 16,817 and 6,391,452. Formulations that include a compound of Formula (I), (la) or (lb) are prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. See, for example, Ansel, H. C. et al, Pharmaceutical Dosage Forms and Drug Delivery Systems, Sixth Ed. (1995). Preferably these compositions and formulations are prepared with suitable nontoxic pharmaceutically acceptable ingredients. These ingredients are known to those skilled in the preparation of nasal dosage forms and some of these can be found in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, 21st edition, 2005. The choice of suitable carriers is dependent upon the exact nature of the nasal dosage form desired, e.g., solutions, suspensions, ointments, or gels. Nasal dosage forms generally contain large amounts of water in addition to the active ingredient. Minor amounts of other ingredients such as pH adjusters, emulsifiers or dispersing agents, preservatives, surfactants, gelling agents, or buffering and other stabilizing and solubilizing agents are optionally present. Preferably, the nasal dosage form should be isotonic with nasal secretions.

[00215] Pharmaceutical preparations for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium

carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrating agents are added, such as the cross-linked croscarmellose sodium,

polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. In some embodiments, dyestuffs or pigments are added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[00216] In some embodiments, pharmaceutical formulations of a compound of Formula (I), (la) or (lb) and/or an additional therapeutic agent, are in the form of a capsules, including push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. A capsule may be prepared, for example, by placing the bulk blend of the formulation of the compound described above, inside of a capsule. In some embodiments, the formulations (non -aqueous suspensions and solutions) are placed in a soft gelatin capsule. In other embodiments, the formulations are placed in standard gelatin capsules or non-gelatin capsules such as capsules comprising HPMC. In other embodiments, the formulation is placed in a sprinkle capsule, wherein the capsule is swallowed whole or the capsule is opened and the contents sprinkled on food prior to eating.

[00217] All formulations for oral administration are in dosages suitable for such administration.

[00218] In one aspect, solid oral dosage forms are prepared by mixing a compound of Formula (I), (la) or (lb) and/or an additional therapeutic agent with one or more of the following: antioxidants, flavoring agents, and carrier materials such as binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, and diluents.

[00219] In some embodiments, the solid dosage forms disclosed herein are in the form of a tablet, (including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid-disintegration tablet, an effervescent tablet, or a caplet), a pill, a powder, a capsule, solid dispersion, solid solution, bioerodible dosage form, controlled release formulations, pulsatile release dosage forms, multiparticulate dosage forms, beads, pellets, granules. In other embodiments, the pharmaceutical formulation is in the form of a powder.

[00220] Compressed tablets are solid dosage forms prepared by compacting the bulk blend of the formulations described above. In various embodiments, tablets will include one or more flavoring agents.

[00221] In other embodiments, the tablets will include a film surrounding the final compressed tablet. In some embodiments, the film coating can provide a delayed release of the compound of Formula (I), (la) or (lb) from the formulation. In other embodiments, the film coating aids in patient compliance (e.g., Opadry^® coatings or sugar coating). Film coatings including Opadry^® typically range from about 1% to about 3% of the tablet weight. [00222] In some embodiments, solid dosage forms, e.g., tablets, effervescent tablets, and capsules, are prepared by mixing particles of a compound with one or more pharmaceutical excipients to form a bulk blend composition. The bulk blend is readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules. In some embodiments, the individual unit dosages include film coatings. These formulations are manufactured by conventional formulation techniques.

[00223] In another aspect, dosage forms include microencapsulated formulations. In some embodiments, one or more other compatible materials are present in the microencapsulation material. Exemplary materials include, but are not limited to, pH modifiers, erosion facilitators, anti-foaming agents, antioxidants, flavoring agents, and carrier materials such as binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, and diluents.

[00224] Exemplary useful microencapsulation materials include, but are not limited to, hydroxypropyl cellulose ethers (HPC) such as Klucel® or Nisso HPC, low-substituted hydroxypropyl cellulose ethers (L- HPC), hydroxypropyl methyl cellulose ethers (HPMC) such as Seppifilm-LC, Pharmacoat®, Metolose SR, Methocel®-E, Opadry YS, PrimaFlo, Benecel MP824, and Benecel MP843, methylcellulose polymers such as Methocel®-A, hydroxypropylmethylcellulose acetate stearate Aqoat (HF-LS, HF-LG,HF-MS) and

Metolose®, Ethylcelluloses (EC) and mixtures thereof such as E461, Ethocel®, Aqualon®-EC, Surelease®, Polyvinyl alcohol (PVA) such as Opadry AMB, hydroxyethylcelluloses such as Natrosol®,

carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC) such as Aqualon®-CMC, polyvinyl alcohol and polyethylene glycol co-polymers such as Kollicoat IR®, monoglycerides (Myverol), triglycerides (KLX), polyethylene glycols, modified food starch, acrylic polymers and mixtures of acrylic polymers with cellulose ethers such as Eudragit® EPO, Eudragit® L30D-55, Eudragit® FS 30D Eudragit® L100-55, Eudragit® L100, Eudragit® S 100, Eudragit® RD 100, Eudragit® E100, Eudragit® L12.5, Eudragit® S 12.5, Eudragit® NE30D, and Eudragit® NE 40D, cellulose acetate phthalate, sepifilms such as mixtures of HPMC and stearic acid, cyclodextrins, and mixtures of these materials.

[00225] Liquid formulation dosage forms for oral administration are optionally aqueous suspensions selected from the group including, but not limited to, pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups. See, e.g., Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. 754-757 (2002). In addition to an antibacterial compound the liquid dosage forms optionally include additives, such as: (a) disintegrating agents; (b) dispersing agents; (c) wetting agents; (d) at least one preservative, (e) viscosity enhancing agents, (f) at least one sweetening agent, and (g) at least one flavoring agent. In some embodiments, the aqueous dispersions further includes a crystal -forming inhibitor.

[00226] In some embodiments, the pharmaceutical formulations described herein are self-emulsifying drug delivery systems (SEDDS). Emulsions are dispersions of one immiscible phase in another, usually in the form of droplets. Generally, emulsions are created by vigorous mechanical dispersion. SEDDS, as opposed to emulsions or microemulsions, spontaneously form emulsions when added to an excess of water without any external mechanical dispersion or agitation. An advantage of SEDDS is that only gentle mixing is required to distribute the droplets throughout the solution. Additionally, water or the aqueous phase is optionally added just prior to administration, which ensures stability of an unstable or hydrophobic active ingredient. Thus, the SEDDS provides an effective delivery system for oral and parenteral delivery of hydrophobic active ingredients. In some embodiments, SEDDS provides improvements in the bioavailability of hydrophobic active ingredients. Methods of producing self-emulsifying dosage forms include, but are not limited to, for example, U.S. Pat. Nos. 5,858,401, 6,667,048, and 6,960,563.

[00227] Buccal formulations that include a compound of Formula (I), (la) or (lb) are administered using a variety of formulations known in the art. For example, such formulations include, but are not limited to, U.S. Pat. Nos. 4,229,447, 4,596,795, 4,755,386, and 5,739, 136. In addition, the buccal dosage forms described herein can further include a bioerodible (hydrolysable) polymeric carrier that also serves to adhere the dosage form to the buccal mucosa. For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, or gels formulated in a conventional manner.

[00228] For intravenous injections, an antibacterial compound is optionally formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. For other parenteral injections, appropriate formulations include aqueous or nonaqueous solutions, preferably with physiologically compatible buffers or excipients.

[00229] Parenteral injections optionally involve bolus injection or continuous infusion. Formulations for injection are optionally presented in unit dosage form, e.g., in ampoules or in multi dose containers, with an added preservative. In some embodiments, a pharmaceutical composition described herein is in a form suitable for parenteral injection as a sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of an agent that modulates the activity of a carotid body in water soluble form. Additionally, suspensions of an agent that modulates the activity of a carotid body are optionally prepared as appropriate, e.g., oily injection suspensions.

[00230] Conventional formulation techniques include, e.g., one or a combination of methods: ( 1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion. Other methods include, e.g., spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., wurster coating), tangential coating, top spraying, tableting, extruding and the like.

[00231] Suitable carriers for use in the solid dosage forms described herein include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol and the like.

[00232] Suitable filling agents for use in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate,

microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starch, hydroxypropylmethycellulose (HPMC), hydroxypropylmethycellulose phthalate,

hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

[00233] Suitable disintegrants for use in the solid dosage forms described herein include, but are not limited to, natural starch such as corn starch or potato starch, a pregelatinized starch, or sodium starch glycolate, a cellulose such as methylcrystalline cellulose, methylcellulose, microcrystalline cellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium carboxymethylcellulose, cross-linked

carboxymethylcellulose, or cross-linked croscarmellose, a cross-linked starch such as sodium starch glycolate, a cross-linked polymer such as crospovidone, a cross-linked polyvinylpyrrolidone, alginate such as alginic acid or a salt of alginic acid such as sodium alginate, a gum such as agar, guar, locust bean, Karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, sodium lauryl sulfate, sodium lauryl sulfate in combination starch, and the like.

[00234] Binders impart cohesiveness to solid oral dosage form formulations: for powder filled capsule formulation, they aid in plug formation that can be filled into soft or hard shell capsules and for tablet formulation, they ensure the tablet remaining intact after compression and help assure blend uniformity prior to a compression or fill step. Materials suitable for use as binders in the solid dosage forms described herein include, but are not limited to, carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, hydroxyethylcellulose, hydroxypropylcellulose, ethylcellulose, and microcrystalline cellulose, microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acids, bentonites, gelatin, polyvinylpyrrolidone/vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, a sugar, such as sucrose, glucose, dextrose, molasses, mannitol, sorbitol, xylitol, lactose, a natural or synthetic gum such as acacia, tragacanth, ghatti gum, mucilage of isapol husks, starch, polyvinylpyrrolidone, larch arabogalactan, polyethylene glycol, waxes, sodium alginate, and the like.

[00235] In general, binder levels of 20-70% are used in powder-filled gelatin capsule formulations. Binder usage level in tablet formulations varies whether direct compression, wet granulation, roller compaction, or usage of other excipients such as fillers which itself can act as moderate binder. Binder levels of up to 70% in tablet formulations is common.

[00236] Suitable lubricants or glidants for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumerate, alkali -metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, magnesium stearate, zinc stearate, waxes, Stearowet^®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol or a methoxypolyethylene glycol such as Carbowax™, PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium or sodium lauryl sulfate, and the like. [00237] Suitable diluents for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose, and dextrose), polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins and the like.

[00238] Suitable wetting agents for use in the solid dosage forms described herein include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate,

polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (e.g., Polyquat 10^®), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, triacetin, vitamin E TPGS and the like.

[00239] Suitable surfactants for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic^® (BASF), and the like.

[00240] Suitable suspending agents for use in the solid dosage forms described here include, but are not limited to, polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17,

polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyethylene glycol, e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400, vinyl pyrrolidone/vinyl acetate copolymer (S630), sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as, e.g., gum tragacanth and gum acacia, guar gum, xanthans, including xanthan gum, sugars, cellulosics, such as, e.g., sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose,

hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone and the like.

[00241] Suitable antioxidants for use in the solid dosage forms described herein include, for example, e.g., butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.

[00242] It should be appreciated that there is considerable overlap between additives used in the solid dosage forms described herein. Thus, the above-listed additives should be taken as merely exemplary, and not limiting, of the types of additives that can be included in solid dosage forms of the pharmaceutical compositions described herein. The amounts of such additives can be readily determined by one skilled in the art, according to the particular properties desired.

[00243] In various embodiments, the particles of a compound of Formula (I), (la) or (lb) and one or more excipients are dry blended and compressed into a mass, such as a tablet, having a hardness sufficient to provide a pharmaceutical composition that substantially disintegrates within less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes, after oral administration, thereby releasing the formulation into the gastrointestinal fluid.

[00244] In other embodiments, a powder including a compound of Formula (I), (la) or (lb) is formulated to include one or more pharmaceutical excipients and flavors. Such a powder is prepared, for example, by mixing the compound and optional pharmaceutical excipients to form a bulk blend composition. Additional embodiments also include a suspending agent and/or a wetting agent. This bulk blend is uniformly subdivided into unit dosage packaging or multi -dosage packaging units.

[00245] In still other embodiments, effervescent powders are also prepared. Effervescent salts have been used to disperse medicines in water for oral administration.

[00246] Controlled release formulations

[00247] In some embodiments, the pharmaceutical dosage forms are formulated to provide a controlled release of a compound of Formula (I), (la) or (lb) and/or an additional therapeutic agent. Additional therapeutic agents include antibacterial compounds and antibodies, such as those described herein. Controlled release refers to the release of the compound from a dosage form in which it is incorporated according to a desired profile over an extended period of time. Controlled release profiles include, for example, sustained release, prolonged release, pulsatile release, and delayed release profiles. In contrast to immediate release

compositions, controlled release compositions allow delivery of an agent to a subject over an extended period of time according to a predetermined profile. Such release rates can provide therapeutically effective levels of agent for an extended period of time and thereby provide a longer period of pharmacologic response while minimizing side effects as compared to conventional rapid release dosage forms. Such longer periods of response provide for many inherent benefits that are not achieved with the corresponding short acting, immediate release preparations.

[00248] In some embodiments, the solid dosage forms described herein are formulated as enteric coated delayed release oral dosage forms, i.e., as an oral dosage form of a pharmaceutical composition as described herein which utilizes an enteric coating to affect release in the small intestine or large intestine. In one aspect, the enteric coated dosage form is a compressed or molded or extruded tablet/mold (coated or uncoated) containing granules, powder, pellets, beads or particles of the active ingredient and/or other composition components, which are themselves coated or uncoated. In one aspect, the enteric coated oral dosage form is in the form of a capsule containing pellets, beads or granules, which include a compound of Formula (I), (la) or (lb), that are coated or uncoated.

[00249] Any coatings should be applied to a sufficient thickness such that the entire coating does not dissolve in the gastrointestinal fluids at pH below about 5, but does dissolve at pH about 5 and above. Coatings are typically selected from any of the following:

[00250] Shellac - this coating dissolves in media of pH >7; Acrylic polymers - examples of suitable acrylic polymers include methacrylic acid copolymers and ammonium methacrylate copolymers. The Eudragit series E, L, S, RL, RS and NE (Rohm Pharma) are available as solubilized in organic solvent, aqueous dispersion, or dry powders. The Eudragit series RL, NE, and RS are insoluble in the gastrointestinal tract but are permeable and are used primarily for colonic targeting. The Eudragit series E dissolve in the stomach. The Eudragit series L, L-30D and S are insoluble in stomach and dissolve in the intestine; Poly Vinyl Acetate Phthalate (PVAP) - PVAP dissolves in pH >5, and it is much less permeable to water vapor and gastric fluids. [00251] Conventional coating techniques such as spray or pan coating are employed to apply coatings. The coating thickness must be sufficient to ensure that the oral dosage form remains intact until the desired site of topical delivery in the intestinal tract is reached.

[00252] In other embodiments, the formulations described herein are delivered using a pulsatile dosage form. A pulsatile dosage form is capable of providing one or more immediate release pulses at predetermined time points after a controlled lag time or at specific sites. Exemplary pulsatile dosage forms and methods of their manufacture are disclosed in U.S. Pat. Nos. 5,01 1,692, 5,017,381, 5,229, 135, 5,840,329 and 5,837,284. In one embodiment, the pulsatile dosage form includes at least two groups of particles, (i.e. multiparticulate) each containing the formulation described herein. The first group of particles provides a substantially immediate dose of the compound of Formula (I), (la) or (lb) upon ingestion by a mammal. The first group of particles can be either uncoated or include a coating and/or sealant. In one aspect, the second group of particles comprises coated particles. The coating on the second group of particles provides a delay of from about 2 hours to about 7 hours following ingestion before release of the second dose. Suitable coatings for pharmaceutical compositions are described herein or known in the art.

[00253] In some embodiments, pharmaceutical formulations are provided that include particles of a compound of Formula (I), (la) or (lb) and at least one dispersing agent or suspending agent for oral administration to a subject. The formulations may be a powder and/or granules for suspension, and upon admixture with water, a substantially uniform suspension is obtained.

[00254] In some embodiments, particles formulated for controlled release are incorporated in a gel or a patch or a wound dressing.

[00255] In one aspect, liquid formulation dosage forms for oral administration and/or for topical

administration as a wash are in the form of aqueous suspensions selected from the group including, but not limited to, pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups. See, e.g., Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. 754-757 (2002). In addition to the particles of a compound of Formula (I), (la) or (lb), the liquid dosage forms include additives, such as: (a) disintegrating agents; (b) dispersing agents; (c) wetting agents; (d) at least one preservative, (e) viscosity enhancing agents, (f) at least one sweetening agent, and (g) at least one flavoring agent. In some embodiments, the aqueous dispersions can further include a crystalline inhibitor.

[00256] In some embodiments, the liquid formulations also include inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers. Exemplary emulsifiers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3 - butyleneglycol, dimethylformamide, sodium lauryl sulfate, sodium doccusate, cholesterol, cholesterol esters, taurocholic acid, phosphotidylcholine, oils, such as cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acid esters of sorbitan, or mixtures of these substances, and the like.

[00257] Furthermore, pharmaceutical compositions optionally include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.

[00258] Additionally, pharmaceutical compositions optionally include one or more salts in an amount required to bring osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

[00259] Other pharmaceutical compositions optionally include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury -containing substances such as merfen and thiomersal;

stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

[00260] In one embodiment, the aqueous suspensions and dispersions described herein remain in a homogenous state, as defined in The USP Pharmacists' Pharmacopeia (2005 edition, chapter 905), for at least 4 hours. In one embodiment, an aqueous suspension is re-suspended into a homogenous suspension by physical agitation lasting less than 1 minute. In still another embodiment, no agitation is necessary to maintain a homogeneous aqueous dispersion.

[00261] Examples of disintegrating agents for use in the aqueous suspensions and dispersions include, but are not limited to, a starch, e.g., a natural starch such as corn starch or potato starch, a pregelatinized starch, or sodium starch glycolate; a cellulose such as methylcrystalline cellulose, methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium carboxymethylcellulose, cross-linked

carboxymethylcellulose, or cross-linked croscarmellose; a cross-linked starch such as sodium starch glycolate; a cross-linked polymer such as crospovidone; a cross-linked polyvinylpyrrolidone; alginate such as alginic acid or a salt of alginic acid such as sodium alginate; a gum such as agar, guar, locust bean, Karaya, pectin, or tragacanth; sodium starch glycolate; bentonite; a natural sponge; a surfactant; a resin such as a cation- exchange resin; citrus pulp; sodium lauryl sulfate; sodium lauryl sulfate in combination starch; and the like.

[00262] In some embodiments, the dispersing agents suitable for the aqueous suspensions and dispersions described herein include, for example, hydrophilic polymers, electrolytes, Tween ^® 60 or 80, PEG, polyvinylpyrrolidone, and the carbohydrate -based dispersing agents such as, for example,

hydroxypropylcellulose and hydroxypropyl cellulose ethers, hydroxypropyl methylcellulose and

hydroxypropyl methylcellulose ethers, carboxymethylcellulose sodium, methylcellulose,

hydroxyethylcellulose, hydroxypropylmethyl-cellulose phthalate, hydroxypropylmethyl-cellulose acetate stearate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), polyvinylpyrrolidone/vinyl acetate copolymer, 4-(l, l,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers; and poloxamines. In other embodiments, the dispersing agent is selected from a group not comprising one of the following agents: hydrophilic polymers; electrolytes; Tween^® 60 or 80; PEG; polyvinylpyrrolidone (PVP); hydroxypropylcellulose and hydroxypropyl cellulose ethers; hydroxypropyl methylcellulose and hydroxypropyl methylcellulose ethers;

carboxymethylcellulose sodium; methylcellulose; hydroxyethylcellulose; hydroxypropylmethyl -cellulose phthalate; hydroxypropylmethyl-cellulose acetate stearate; non-crystalline cellulose; magnesium aluminum silicate; triethanolamine; polyvinyl alcohol (PVA); 4-(l, l,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde; poloxamers; or poloxamines.

[00263] Wetting agents suitable for the aqueous suspensions and dispersions described herein include, but are not limited to, cetyl alcohol, glycerol monostearate, polyoxyethylene sorbitan fatty acid esters (e.g., the commercially available Tweens^® such as e.g., Tween 20^® and Tween 80^®, and polyethylene glycols, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate,

polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium oleate, sodium lauryl sulfate, sodium docusate, triacetin, vitamin E TPGS, sodium taurocholate, simethicone, phosphotidylcholine and the like.

[00264] Suitable preservatives for the aqueous suspensions or dispersions described herein include, for example, potassium sorbate, parabens (e.g., methylparaben and propylparaben), benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl alcohol or benzyl alcohol, phenolic compounds such as phenol, or quaternary compounds such as benzalkonium chloride. Preservatives, as used herein, are incorporated into the dosage form at a concentration sufficient to inhibit microbial growth.

[00265] Suitable viscosity enhancing agents for the aqueous suspensions or dispersions described herein include, but are not limited to, methyl cellulose, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, Plasdon^® S-630, carbomer, polyvinyl alcohol, alginates, acacia, chitosans and combinations thereof. The concentration of the viscosity enhancing agent will depend upon the agent selected and the viscosity desired.

[00266] Examples of sweetening agents suitable for the aqueous suspensions or dispersions described herein include, for example, acacia syrup, acesulfame K, alitame, aspartame, chocolate, cinnamon, citrus, cocoa, cyclamate, dextrose, fructose, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, monoammonium glyrrhizinate (MagnaSweet^®), malitol, mannitol, menthol, neohesperidine DC, neotame, Prosweet^® Powder, saccharin, sorbitol, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, sucralose, tagatose, thaumatin, vanilla, xylitol, or any combination thereof.

[00267] Certain topical compositions

[00268] In some embodiments, compounds of Formula (I), (la) or (lb) and/or an additional therapeutic agent are prepared as transdermal dosage forms. Additional therapeutic agents include antibacterial compounds and antibodies, such as those described herein. In one embodiment, the transdermal formulations described herein include at least three components: ( 1) a formulation of a compound of Formula (I), (la) or (lb); (2) a penetration enhancer; and (3) an optional aqueous adjuvant. In some embodiments the transdermal formulations include additional components such as, but not limited to, gelling agents, creams and ointment bases, and the like. In some embodiments, the transdermal formulation is presented as a patch or a wound dressing. In some embodiments, the transdermal formulation further include a woven or non-woven backing material to enhance absorption and prevent the removal of the transdermal formulation from the skin. In other embodiments, the transdermal formulations described herein can maintain a saturated or supersaturated state to promote diffusion into the skin.

[00269] In one aspect, formulations suitable for transdermal administration of compounds described herein employ transdermal delivery devices and transdermal delivery patches and can be lipophilic emulsions or buffered, aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive. In one aspect, such patches are constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. Still further, transdermal delivery of the compounds described herein can be accomplished by means of iontophoretic patches and the like. In one aspect, transdermal patches provide controlled delivery of a compound of Formula (I), (la) or (lb). In one aspect, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.

[00270] In further embodiments, topical formulations include gel formulations (e.g., gel patches which adhere to the skin). In some of such embodiments, a gel composition includes any polymer that forms a gel upon contact with the body (e.g., gel formulations comprising hyaluronic acid, pluronic polymers, poly(lactic-co- glycolic acid (PLGA)-based polymers or the like). In some forms of the compositions, the formulation comprises a low -melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter which is first melted. Optionally, the formulations further comprise a moisturizing agent.

[00271] In certain embodiments, delivery systems for pharmaceutical compounds may be employed, such as, for example, liposomes and emulsions. In certain embodiments, compositions provided herein can also include an mucoadhesive polymer, selected from among, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran.

[00272] In some embodiments, the compounds described herein may be administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments. Such pharmaceutical compounds can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

[00273] In alternative embodiments, a compound of Formula (I), (la) or (lb) is formulated and presented as a wash or rinse liquid which is used to irrigate the affected area. In further embodiments, a compound of Formula (I), (la) or (lb) is formulated and presented as a spray which is applied to the affected area. Further Embodiments

1. An embodiment of a method for treating a bacterial infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of an antibacterial compound of Formula (I)

Formula (I)

or pharmaceutically acceptable salt or solvate thereof, wherein:

R¹ and R³ are independently selected from substituted or unsubstituted Ci-Ci₀alkyl, substituted or unsubstituted C₃-Ci₀cycloalkyl, substituted or unsubstituted C₂-Ci₀heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, wherein if R¹ and R³ are substituted then R¹ and R³ are independently substituted with one or more R⁴ groups; each R⁴ is independently selected from D, -OR⁵, -SR⁵, -F, -CI, -Br, -I, -C(0)R⁵, -C0₂R⁵, -CN, - N0₂, -N(R⁶)(R⁷), substituted or unsubstituted Ci-C₇alkyl, substituted or unsubstituted C₃- C₇cycloalkyl, substituted or unsubstituted C₂-C₆heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

R² is independently selected from H, substituted or unsubstituted Ci-C₇alkyl, substituted or

unsubstituted C₃-C₇cycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted benzyl;

X and Y are independently selected from -0-, -S-, and (-CR⁸R⁹-)_n; wherein each R⁸ and R⁹ are

independently selected from H, -F, -CI, -Br, -I, -OR⁵, -C(0)R⁵, substituted or unsubstituted Ci- C₇alkyl; substituted or unsubstituted C₃-C₇cycloalkyl, substituted or unsubstituted C₂- C₇heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; n is 1, 2, 3, or 4. The method of embodiment 1, wherein the antibacterial compound of Formula (I) has the structure of Formula (la)

Formula (la)

or pharmaceutically acceptable salt or solvate thereof, wherein:

X¹, X², X³, X⁴, and X⁵ are independently selected from N, CH, and CR⁴;

Y¹, Y², Y³, Y⁴, and Y⁵ are independently selected from N, CH, and CR⁴;

p is 0, 1, 2, 3, 4 or 5.

The method of embodiment 2, wherein the antibacterial compound of Formula (la) has the structure of Formula (lb)

Formula (lb)

or pharmaceutically acceptable salt or solvate thereof, wherein:

each R⁴ is independently selected from H, substituted or unsubstituted Ci-C₇alkyl which may

optionally be substituted with -F, -OH, and -OMe, and C₃-C₇cycloalkyl;

R⁸ and R⁹ are independently selected from -H and Ci-C₇alkyl or R⁴ and R⁵ are taken together to form a C₃-C₇cycloalkyl;

additionally or alternatively, one of R⁴ may be taken together with one of R⁸ or R⁹ to form a C₅- Cncycloalkyl ring.

The method of embodiment 3, wherein the antibacterial compound of Formula (lb) has the structure of avasimibe

or pharmaceutically acceptable salt or solvate thereof. The method of any of embodiments 1-4, wherein a causative agent of the bacterial infection is a Gram-positive bacteria, and the subject is infected with the causative agent.

The method of embodiment 5, wherein the Gram -positive bacteria is selected from the genus

Staphylococcus, Bacillus, Enterococcus , Streptococcus, and Clostridium.

The method of embodiment 5, wherein the Gram -positive bacteria is selected from Staphylococcus aureus, Staphylococcus epidermidis, Bacillus subtilis, Enterococcus faecium, Streptococcus pneumonia, Streptococcus pyogenes, and Clostridium difficile.

The method of any of embodiments 1-4, wherein a causative agent of the bacterial infection is a Gram-negative bacteria, and the subject is infected with the causative agent.

The method of embodiment 8, wherein the Gram-negative bacteria is selected from the genus

Pseudomonas, Escherichia, Haemophilus, Acinetobacter, and Klebsiella.

The method of embodiment 8, wherein the Gram-negative bacteria is selected from Pseudomonas aeruginosa, Escherichia coli, Haemophilus influenzae, Acinetobacter baumannii, and Klebsiella pneumonia.

The method of any of embodiments 5-7, wherein the Gram-positive bacteria has resistance to a drug. The method of any of embodiments 8-10, wherein the Gram-negative bacteria has resistance to a drug. The method of any of embodiments 1-4, wherein a causative agent of the bacterial infection is a bacteria having resistance to a drug.

The method of any of embodiments 11-13, wherein the drug is an antibiotic.

The method of embodiment 14, wherein the antibiotic is a polymyxin antibiotic.

The method of embodiment 15, wherein the polymyxin antibiotic comprises polymyxin B and/or colistin.

The method of embodiment 14, wherein the antibiotic is a beta-lactam antibiotic.

The method of embodiment 17, wherein the beta-lactam antibiotic comprises penicillin, methicillin, oxacillin, nafcillin, ampicillin, amoxicillin, carbenicillin or a combination thereof.

The method of embodiment 14, wherein the antibiotic is a fluoroquinolone antibiotic.

The method of embodiment 14, wherein the antibiotic is a cephalosporin antibiotic.

The method of embodiment 14, wherein the antibiotic is a carbapenem antibiotic.

The method of embodiment 14, wherein the antibiotic comprises methicillin, vancomycin, erythromycin, doxycycline, tetracycline, linezolid, clindamycin, ceftriazone, or a combination thereof. The method of any of embodiments 5-23, wherein treating the bacterial infection comprises reducing the population of viable causative agent in the subject as compared to the population of viable causative agent in the subject prior to administration of the antibacterial compound of Formula (I). The method of embodiment 24, wherein the population of viable causative agent in the subject is reduced by at least about 20%, 40%, 60%, 80% or 90% after administration of the antibacterial compound of Formula (I). The method of embodiment 24 or embodiment 25, wherein the population of viable causative agent in the subject is reduced within 1, 2, 3, 4, 5, 6 or 7 days of a first dose of the administration of the antibacterial compound of Formula (I).

The method of any of embodiments 5-26, wherein treating the bacterial infection comprises reducing growth, replication and/or propagation of the causative agent in the subject by at least about 20%, 40%, 60%, 80% or 90% after administration of the antibacterial compound of Formula (I).

The method of embodiment 27, wherein the reduction in growth, replication and/or propagation of the causative agent in the subject is reduced by at least about 20%, 40%, 60%, 80% or 90% after administration of the antibacterial compound of Formula (I).

The method of embodiment 27 or embodiment 28, wherein the growth, replication and/or propagation of the causative agent in the subject is reduced within 1, 2, 3, 4, 5, 6 or 7 days of a first dose of the administration of the antibacterial compound of Formula (I).

The method of any of embodiments 5-29, wherein treating the bacterial infection comprises reducing a symptom and/or complication of the bacterial infection presenting in the subject, as compared to the symptom and/or complication prior to the administration of the antibacterial compound of Formula (I). The method of embodiment 30, wherein the symptom and/or complication of the bacterial infection is reduced by at least about 20%, 40%, 60%, 80% or 90%.

The method of embodiment 30 or embodiment 31, wherein the symptom and/or complication of the bacterial infection is reduced within 1, 2, 3, 4, 5, 6 or 7 days of a first dose of the administration of the antibacterial compound of Formula (I).

The method of any of embodiments 1-32, wherein the antibacterial compound of Formula (I) is administered in one or more doses totaling 1-1,000 mg per day.

The method of any of embodiments 1-33, wherein the antibacterial compound of Formula (I) is administered 1, 2, 3 or 4 times a day.

The method of any of embodiments 1-34, wherein the antibacterial compound of Formula (I) is administered over a course of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 days.

The method of any of embodiments 1-35, wherein the antibacterial compound of Formula (I) is intravenously administered.

The method of any of embodiments 1-35, wherein the antibacterial compound of Formula (I) is administered by nasogastric or orogastric intubation.

The method of any of embodiments 1-35, wherein the antibacterial compound of Formula (I) is orally administered.

The method of any of embodiments 1-38, wherein the subject is administered an additional antibacterial compound.

The method of embodiment 39, wherein the additional antibacterial compound is administered with the antibacterial compound of Formula (I). The method of embodiment 39, wherein the additional antibacterial compound is administered separately from the antibacterial compound of Formula (I).

The method of embodiment 39 or embodiment 40, wherein the additional antibacterial compound is administered in a separate composition than the antibacterial compound of Formula (I).

The method of any of embodiments 39-42, wherein the additional antibacterial compound comprises an aminoglycoside.

The method of embodiment 43, wherein the aminoglycoside comprises kanamycin, amikacin, apramycin, arbekacin, astromicin, bekanamycin, capreomycin, dibekacin, dihydrostreptomycin, elsamitrucin, fosfomycin, tobramycin, g418, gentamicin, hygromycin b, isepamicin, kanamycin, kasugamycin, legonmycin, lividomycin, micronomicin, neamine, neomycin, netilmicin,

nourseothricin, paromomycin, plazomicin, ribostamycin, sisomicin, streptoduocin, streptomycin, tobramycin, totomycin, verdamicin or a combination thereof.

The method of embodiment 1, wherein the compound of Formula (I) is administered to treat infection of the subject with S. aureus.

The method of embodiment 1, wherein the compound of Formula (I) is administered to prevent infection of the subject with S. aureus.

The method of any of embodiments 1-46, wherein the compound of Formula (I) is administered prior to, during, and/or within 1 year of the subject undergoing a medical procedure.

The method of embodiment 47, wherein the medical procedure comprises a surgery.

The method of embodiment 47 or embodiment 48, wherein the medical procedure comprises the subject receiving an implant.

The method of embodiment 49, wherein the implant is an orthopedic implant.

The method of embodiment 50, wherein the orthopedic implant is a joint prosthesis, graft or synthetic implant.

The method of any of embodiments 1-51, wherein the bacterial infection is in a bone of the subject and/or within a 1 inch region of the bone of the subject.

The method of embodiment 52, wherein the subject has osteomyelitis.

The method of any of embodiments 1-53, wherein the bacterial infection is a periprosthetic infection. The method of any of embodiments 1-54, wherein the subject is immunocompromised.

The method of embodiment 55, wherein the subject has Human Immunodeficiency Virus (HIV) or acquired immune deficiency syndrome (AIDS).

The method of any of embodiments 1-56, wherein the subject is administered an antibody or an antigen-binding fragment of the antibody.

The method of embodiment 57, wherein the antibody or the antigen-binding fragment of the antibody is administered with the antibacterial compound of Formula (I).

The method of embodiment 57, wherein the antibody or the antigen-binding fragment of the antibody is administered separately from the antibacterial compound of Formula (I). 60. The method of any of embodiments 57-59, wherein the antibody or the antigen-binding fragment of the antibody is administered in a separate composition from the antibacterial compound of Formula (I).

61. The method of any of embodiments 57-60, wherein the antibody or the antigen-binding fragment of the antibody is administered as a vaccine to prevent the bacterial infection.

62. The method of embodiment 61, wherein the subject is an individual who has a greater risk than the general population for developing the bacterial infection.

63. The method of any of embodiments 57-62, wherein the antibody or the antigen-binding fragment of the antibody is administered during passive immunization.

64. The method of any of embodiments 1-63, wherein the antibody or the antigen-binding fragment of the antibody is administered for the treatment of active bacterial infection.

65. The method of any of embodiments 57-64, wherein the antibody is administered during active

immunization.

66. The method of any of embodiments 57-65, wherein the antibody or the antigen-binding fragment of the antibody binds to a peptide or portion thereof from a bacteria selected from Staphylococcus, Bacillus, Enter ococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, and Klebsiella.

67. The method of embodiment 66, wherein the antibody or the antigen-binding fragment of the antibody promotes lysis of the bacteria.

68. The method of embodiment 66 or embodiment 67, wherein the bacteria is drug-resistant.

69. The method of embodiment 68, wherein the bacteria is methicillin resistant.

70. The method of any of embodiments 57-69, wherein the antibody is a monoclonal antibody.

71. The method of any of embodiments 57-70, wherein the antibody is humanized.

72. The method of any of embodiments 57-71, wherein the antibody or the antigen-binding fragment of the antibody binds to an autolysin or fragment thereof.

73. The method of embodiment 72, wherein the autolysin is from a bacteria selected from Staphylococcus, Bacillus, Enter ococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, and Klebsiella.

74. The method of embodiment 73, wherein the bacteria is Stapylococcus .

75. The method of any of embodiments 72-74, wherein the antibody or the antigen-binding fragment of the antibody at least partially or wholly binds to the glucosaminidase subunit of the autolysin, or a fragment of the glucosaminidase subunit.

76. The method of embodiment 75, wherein the glucosaminidase comprises the sequence of SEQ ID NO:

1.

77. The method of embodiment 75, wherein the antibody or the antigen-binding fragment of the antibody binds to an epitope at least partially positioned within the glucosaminidase R3 domain. 78. The method of any of embodiments 75-77, wherein the glucosaminidase is a Staphylococcus aureus glucosaminidase.

79. The method of embodiment 75 or embodiment 76, wherein the antibody or the antigen-binding

fragment of the antibody binds to an epitope within the glucosaminidase catalytic domain.

80. The method of any of embodiments 75-79, wherein the antibody or the antigen-binding fragment of the antibody inhibits activity of the glucosaminidase.

81. The method of any of embodiments 72-80, wherein the antibody or the antigen-binding fragment of the antibody comprises a variable domain sequence at least 80%, 85%, 90%, 95%, or 99%

homologous to a sequence selected from SEQ ID NO: 2-13.

82. The method of embodiment 81, wherein the antibody or the antigen-binding fragment of the antibody comprises one or more CDRs selected from SEQ ID NOS: 2-13.

83. The method of any of embodiments 72-82, wherein the antibody or the antigen-binding fragment of the antibody comprises the sequences of amino acid residues 31 -35, 50-66, and 99-1 10 of SEQ ID NO: 6 and/or the sequence of amino acid residues 24-31, 50-56, and 89-95 of SEQ ID NO: 1 1.

84. The method of any of embodiments 57-71, wherein the antibody or the antigen-binding fragment of the antibody binds to a bacterial autolysin N-acetylmuramoyl-L-alanine amidase catalytic domain or a fragment or portion thereof.

85. The method of embodiment 84, wherein the bacterial autolysin N-acetylmuramoyl-L-alanine amidase catalytic domain is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus ,

Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

86. The method of any of embodiments 57-71, wherein the antibody or the antigen-binding fragment of the antibody binds to a bacterial cell wall binding domain, or a fragment or portion thereof.

87. The method of embodiment 86, wherein the bacterial cell wall binding domain is from a bacteria

selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

88. The method of any of embodiments 57-71, wherein the antibody or the antigen-binding fragment of the antibody binds to a bacterial cell surface-associated antigen, or a fragment or portion thereof.

89. The method of embodiment 88, wherein the bacterial cell surface-associated antigen is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

90. The method of any of embodiments 57-71, wherein the antibody or the antigen-binding fragment of the antibody binds to a bacterial exotoxin, or a fragment or portion thereof.

91. The method of embodiment 90, wherein the bacterial exotoxin is from a bacteria selected from

Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof. 92. The method of any of embodiments 57-71, wherein the antibody or the antigen-binding fragment of the antibody binds to a bacterial protease, or a fragment or portion thereof.

93. The method of embodiment 92, wherein the bacterial protease is V8 protease, a member of the glutamyl endopeptidase I family of Staphylococcus aureus V8 strain (GluV8), or a fragment or portion thereof.

94. The method of embodiment 92, wherein the bacterial protease is from a bacteria selected from

Staphylococcus, Bacillus, Enterococcus , Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

95. The method of any of embodiments 57-94, wherein the antibody or the antigen-binding fragment of the antibody binds to a bacterial leucocidin, or a fragment or portion thereof.

96. The method of embodiment 95, wherein the bacterial leucocidin is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

97. The method of any of embodiments 57-71, wherein the antibody or the antigen-binding fragment of the antibody binds to a bacterial adhesin, or a fragment or portion thereof.

98. The method of embodiment 97, wherein the bacterial adhesin is from a bacteria selected from

Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

99. The method of embodiment 97 or embodiment 98, wherein the bacterial adhesin is a surface-bound adhesin that promotes host colonization.

100. The method of any of embodiments 57-71, wherein the antibody or the antigen-binding fragment of the antibody binds to a cell surface adhesin that interacts with an extracellular matrix component (microbial surface component recognizing adhesive matrix molecules or MSCRAMMs), or a fragment or portion thereof.

101. The method of any of embodiments 57-71, wherein the antibody or the antigen-binding fragment of the antibody binds to lipoteichoic acid (LTA), or a fragment or portion thereof.

102. The method of embodiment 101, wherein the antibody is pagibaximab (BSYX-A1 10).

103. The method of any of embodiments 57-71, wherein the antibody or the antigen-binding fragment of the antibody binds to Clumping Factor A (ClfA), or a fragment or portion thereof.

104. The method of embodiment 103, wherein the antibody is tefibazumab.

105. The method of embodiment 104, wherein the antibody is Veronate.

106. The method of any of embodiments 57-71, wherein the antibody or the antigen-binding fragment of the antibody binds to ATP -binding cassette (ABC) transporter component GrfA, or a fragment or portion thereof.

107. The method of embodiment 106, wherein the antibody is Aurograb.

108. The method of any of embodiments 57-71, wherein the antibody or the antigen-binding fragment of the antibody binds to poly-N-acetylated glucosamine (PNAG), or a fragment or portion thereof. 109. The method of embodiment 108, wherein the antibody is SAR279356 (F598).

110. The method of any of embodiments 57-71, wherein the antibody or the antigen-binding fragment of the antibody binds to alpha-toxin (AT), or a fragment or portion thereof.

111. The method of embodiment 110, wherein the antibody is MEDI4893.

112. The method of embodiment 110, wherein the antibody is AR-301.

113. The method of any of embodiments 57-71, wherein the antibody or the antigen-binding fragment of the antibody binds to a bacterial molecule selected from an amidase (Amd) protein or polypeptide, an iron-regulated surface determinant protein A (IsdA) protein or polypeptide, an iron-regulated surface determinant protein B (IsdB) protein or polypeptide, an iron-regulated surface determinant protein H (IsdH) protein or polypeptide, a Clumping Factor A (ClfA) protein or polypeptide, a Clumping Factor B (ClfB) protein or polypeptide, a Fibronectin Binding Protein A (FnbpA) protein or polypeptide, a Staphylococcus Complement Inhibitor (SCIN) protein or polypeptide, a Chemotaxis Inhibitory Protein of Staphylococcus aureus (CHIPS) protein or polypeptide, an alpha-Hemolysin (Hla) protein or polypeptide, an Extracellular Fibrinogen-binding (Efb) protein or polypeptide, S pro-toxin subunit from Staphylococcus (LukS-PV) protein or polypeptide, Ser-Asp dipeptide repeat G from (SdrG) protein or polypeptide, staphylococcal enteroxin B (SEB) protein or polypeptide, N-terminus of the candidal surface adhesin (rAls3p-N) protein or polypeptide, extracellular adherence protein (Eap) protein or polypeptide, Serine aspartate repeat containing protein D (SdrD) protein or polypeptide, Serine aspartate repeat containing protein E (SdrE) protein or polypeptide, staphylococcal antigen A (IsaA) protein or polypeptide, protein A or a polypeptide of protein A, panton-valentine leucocidin (PVL) protein or polypeptide, γ-hemolysin C (HlgC) protein or polypeptide, Ferric

hydroxamate-binding lipoprotein (FhuD2) protein or polypeptide, capsular polysaccharide type 5, capsular polysaccharide type 8; or a combination, fragment and/or portion thereof.

114. The method of embodiment 113, wherein the bacterial molecule is from Staphylococcus.

115. The method of embodiment 113, wherein the bacterial molecule is from Staphylococcus aureus.

116. The method of any of embodiments 45-52, wherein the antibody or the antigen-binding fragment of the antibody is selected from Altastaph, Veronate, Aurexis (tefibazumab), pagibaximab (BSYX- A110), Aurograb, SAR279356 (F598), MEDI4893, Salvecin (AR-301, KBSA301), and 514G3 (XBiotech).

117. A method of an embodiment for exerting an antibacterial effect on a bacteria, the method comprising contacting the bacteria with a compound of Formula (I)

Formula (I) or pharmaceutically acceptable salt or solvate thereof, wherein:

R¹ and R³ are independently selected from substituted or unsubstituted Ci-Ci₀alkyl, substituted or unsubstituted C₃-Ci₀cycloalkyl, substituted or unsubstituted C₂-Ci₀heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, wherein if R¹ and R³ are substituted then R¹ and R³ are independently substituted with one or more R⁴ groups;

each R⁴ is independently selected from D, -OR⁵, -SR⁵, -F, -CI, -Br, -I, -C(0)R⁵, -C0₂R⁵, -CN, - N0₂, -N(R⁶)(R⁷), substituted or unsubstituted Ci-C₇alkyl, substituted or unsubstituted C₃- C₇cycloalkyl, substituted or unsubstituted C₂-C₆heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

independently selected from H, -F, -CI, -Br, -I, -OR⁵, -C(0)R⁵, substituted or unsubstituted Ci- C₇alkyl; substituted or unsubstituted C₃-C₇cycloalkyl, substituted or unsubstituted C₂- C₇heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; n is 1, 2, 3, or 4.

The method of embodiment 117, wherein the antibacterial compound of Formula (I) has the structure of Formula (la)

Formula (la)

or pharmaceutically acceptable salt or solvate thereof, wherein:

p is 0, 1, 2, 3, 4 or 5. The method of embodiment 1 18, wherein the antibacterial compound of Formula (la) has the structure of Formula (lb)

Formula (lb)

or pharmaceutically acceptable salt or solvate thereof, wherein:

optionally be substituted with -F, -OH, and -OMe, and C₃-C₇cycloalkyl;

The method of embodiment 1 19, wherein the antibacterial compound of Formula (lb) has the structure of avasimibe

or pharmaceutically acceptable salt or solvate thereof.

121. The method of any of embodiments 1 17-1 19, wherein contacting comprises bringing the bacteria in proximity to the compound of Formula (I) such that the compound of Formula (I) exerts the antibacterial effect on the bacteria.

122. The method of any of embodiments 1 17-120, wherein the antibacterial effect comprises: (i) killing the bacteria, (ii) reducing growth of the bacteria, (iii) reducing replication of the bacteria, (iv) reducing propagation of the bacteria, (v) reducing viable bacteria population, or (vi) a combination of any of (i)-(v).

123. The method of any of embodiments 1 17-122, wherein the antibacterial effect is evaluated by

measuring the minimal inhibitory concentration 50% (MIC50) of the compound of Formula (I) for the bacteria.

124. The method of embodiment 51, wherein the MIC50 is less than about 50 μΜ, 40 μΜ, 30 μΜ, 20 μΜ, 10 μΜ, 1 μΜ, 100 ηΜ, 10 ηΜ, 1 ηΜ, 100 ρΜ or 10 ρΜ. 125. The method of any of embodiments 117-124, wherein contacting comprises administering the compound of Formula (I) to a subject infected with the bacteria.

126. The method of embodiment 125, wherein the compound of Formula (I) is administered orally,

intravenously, subcutaneously or by nasogastric or orogastric intubation.

127. The method of embodiment 125 or embodiment 126, wherein the subject is a human subject or a non- human animal subject.

128. The method of embodiment 127, wherein the non-human animal is a mouse.

129. The method of any of embodiments 117-124, wherein contacting comprises combining the compound of Formula (I) with the bacteria in an in vitro solution.

130. The method of any of embodiments 117-124, wherein contacting comprises providing the compound of Formula (I) on a surface comprising or suspected of comprising the bacteria.

131. The method of any of embodiments 117-130, wherein the bacteria is a Gram -negative bacteria.

132. The method of embodiment 131, wherein the Gram-negative bacteria is selected from the genus

Pseudomonas, Escherichia, Haemophilus, Acinetobacter, and Klebsiella.

133. The method of embodiment 131, wherein the Gram -negative bacteria is selected from Pseudomonas aeruginosa, Escherichia coli, Haemophilus influenzae, Acinetobacter baumannii, and Klebsiella pneumonia.

134. The method of any of embodiments 117-130, wherein the bacteria is a Gram-positive bacteria.

135. The method of embodiment 134, wherein the Gram-positive bacteria is selected from the genus

Staphylococcus, Bacillus, Enterococcus , Streptococcus, and Clostridium.

136. The method of embodiment 134, wherein the Gram-positive bacteria is selected from Staphylococcus aureus, Staphylococcus epidermidis, Bacillus subtilis, Enterococcus faecium, Streptococcus pneumonia, Streptococcus pyogenes, and Clostridium difficile.

137. The method of any of embodiments 117-136, wherein the bacteria has resistance to a drug.

138. The method of embodiment 137, wherein the drug is an antibiotic.

139. The method of embodiment 137, wherein the antibiotic is a polymyxin antibiotic.

140. The method of embodiment 139, wherein the polymyxin antibiotic comprises polymyxin B and/or colistin.

141. The method of embodiment 138, wherein the antibiotic is a beta-lactam antibiotic.

142. The method of embodiment 141, wherein the beta-lactam antibiotic comprises penicillin, methicillin, oxacillin, nafcillin, ampicillin, amoxicillin, carbenicillin or a combination thereof.

143. The method of embodiment 138, wherein the antibiotic is a fluoroquinolone antibiotic.

144. The method of embodiment 138, wherein the antibiotic is a cephalosporin antibiotic.

145. The method of embodiment 138, wherein the antibiotic is a carbapenem antibiotic.

146. The method of embodiment 138, wherein the antibiotic is a cephalosporin antibiotic.

147. The method of embodiment 138, wherein the antibiotic comprises methicillin, vancomycin,

erythromycin, doxycycline, tetracycline, linezolid, clindamycin, ceftriazone, or a combination thereof. 148. The method of any of embodiments 117-147, further comprising contacting the bacteria with an antibacterial compound.

149. The method of embodiment 148, wherein the antibacterial compound comprises an aminoglycoside.

150. The method of embodiment 149, wherein the aminoglycoside comprises kanamycin, amikacin,

apramycin, arbekacin, astromicin, bekanamycin, capreomycin, dibekacin, dihydrostreptomycin, elsamitrucin, fosfomycin, tobramycin, g418, gentamicin, hygromycin b, isepamicin, kanamycin, kasugamycin, legonmycin, lividomycin, micronomicin, neamine, neomycin, netilmicin,

151. The method of embodiment 117, wherein the bacteria is S. aureus.

152. The method of any of embodiments 117-151, further comprising contacting the bacteria with an

antibody or an antigen-binding fragment of the antibody.

153. The method of embodiment 152, wherein the bacteria is contacted with the antibody or the antigen- binding fragment of the antibody prior to contacting the bacteria with the antibacterial compound of Formula (I).

154. The method of embodiment 152, wherein the bacteria is contacted with the antibody or the antigen- binding fragment of the antibody after contacting the bacteria with the antibacterial compound of Formula (I).

155. The method of embodiment 152, wherein the antibody or the antigen-binding fragment of the

antibody contacts the bacteria separately from the antibacterial compound of Formula (I).

156. The method of any of embodiments 152-155, wherein the antibody or the antigen-binding fragment of the antibody prevents infection, growth, or propagation of the bacteria.

157. The method of any of embodiments 152-157, wherein the antibody or the antigen-binding fragment of the antibody promotes lysis of the bacteria.

158. The method of any of embodiments 152-157, wherein the antibody or the antigen-binding fragment of the antibody binds to a peptide or portion thereof from a bacteria selected from Staphylococcus, Bacillus, Enter ococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, and Klebsiella.

159. The method of embodiment 158, wherein the bacteria to which the antibody or the antigen-binding fragment of the antibody binds is drug-resistant.

160. The method of embodiment 158, wherein the drug-resistant bacteria is resistant to methicillin.

161. The method of any of embodiments 152-160, wherein the antibody is a monoclonal antibody.

162. The method of any of embodiments 152-161, wherein the antibody is humanized.

163. The method of any of embodiments 152-162, wherein the antibody or the antigen-binding fragment of the antibody binds to an autolysin or fragment thereof. 164. The method of embodiment 163, wherein the autolysin is from a bacteria selected from

Staphylococcus, Bacillus, Enterococcus , Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, and Klebsiella.

165. The method of embodiment 164, wherein the autolysin is from Stapylococcus .

166. The method of any of embodiments 163-165, wherein the antibody or the antigen-binding fragment of the antibody at least partially or wholly binds to the glucosaminidase subunit of the autolysin, or a fragment of the glucosaminidase subunit.

167. The method of embodiment 166, wherein the glucosaminidase comprises the sequence of SEQ ID NO:

1.

168. The method of embodiment 166, wherein the antibody or the antigen-binding fragment of the

antibody binds to an epitope at least partially positioned within the glucosaminidase R3 domain.

169. The method of any of embodiments 166-168, wherein the glucosaminidase is a Staphylococcus

aureus glucosaminidase.

170. The method of embodiment 166 or embodiment 167, wherein the antibody or the antigen-binding fragment of the antibody binds to an epitope within the glucosaminidase catalytic domain.

171. The method of any of embodiments 166-170, wherein the antibody or the antigen-binding fragment of the antibody inhibits activity of the glucosaminidase.

172. The method of any of embodiments 166-171, wherein the antibody or the antigen-binding fragment of the antibody comprises a variable domain sequence at least 80%, 85%, 90%, 95%, or 99%

homologous to a sequence selected from SEQ ID NO: 2-13.

173. The method of any of embodiments 166-172, wherein the antibody or the antigen-binding fragment of the antibody comprises one or more CDRs selected from SEQ ID NOS: 2-13.

174. The method of any of embodiments 166-173, wherein the antibody or the antigen-binding fragment of the antibody comprises the sequences of amino acid residues 31 -35, 50-66, and 99-1 10 of SEQ ID NO: 6 and/or the sequence of amino acid residues 24-31, 50-56, and 89-95 of SEQ ID NO: 1 1.

175. The method of any of embodiments 152-162, wherein the antibody or the antigen-binding fragment of the antibody binds to a bacterial autolysin N-acetylmuramoyl-L-alanine amidase catalytic domain or a fragment or portion thereof.

176. The method of embodiment 175, wherein the bacterial autolysin N-acetylmuramoyl-L-alanine

amidase catalytic domain is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

177. The method of any of embodiments 152-162, wherein the antibody or the antigen-binding fragment of the antibody binds to a bacterial cell wall binding domain, or a fragment or portion thereof.

178. The method of embodiment 177, wherein the bacterial cell wall binding domain is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof. 179. The method of any of embodiments 152-162, wherein the antibody or the antigen-binding fragment of the antibody binds to a bacterial cell surface-associated antigen, or a fragment or portion thereof.

180. The method of embodiment 179, wherein the bacterial cell surface-associated antigen is from a

bacteria selected from Staphylococcus, Bacillus, Enterococcus , Streptococcus, Clostridium,

181. The method of any of embodiments 152-162, wherein the antibody or the antigen-binding fragment of the antibody binds to a bacterial exotoxin, or a fragment or portion thereof.

182. The method of embodiment 181, wherein the bacterial exotoxin is from a bacteria selected from

183. The method of any of embodiments 152-162, wherein the antibody or the antigen-binding fragment of the antibody binds to a bacterial protease, or a fragment or portion thereof.

184. The method of embodiment 183, wherein the bacterial protease is V8 protease, a member of the

glutamyl endopeptidase I family of Staphylococcus aureus V8 strain (GluV8), or a fragment or portion thereof.

185. The method of embodiment 183, wherein the bacterial protease is from a bacteria selected from

186. The method of any of embodiments 152-162, wherein the antibody or the antigen-binding fragment of the antibody binds to a bacterial leucocidin, or a fragment or portion thereof.

187. The method of embodiment 186, wherein the bacterial leucocidin is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

188. The method of any of embodiments 152-162, wherein the antibody or the antigen-binding fragment of the antibody binds to a bacterial adhesin, or a fragment or portion thereof.

189. The method of embodiment 188, wherein the bacterial adhesin is from a bacteria selected from

190. The method of embodiment 188 or embodiment 189, wherein the bacterial adhesin is a surface -bound adhesin that promotes host colonization.

191. The method of any of embodiments 152-162, wherein the antibody or the antigen-binding fragment of the antibody binds to a cell surface adhesin that interacts with an extracellular matrix component (microbial surface component recognizing adhesive matrix molecules or MSCRAMMs), or a fragment or portion thereof.

192. The method of any of embodiments 152-162, wherein the antibody or the antigen-binding fragment of the antibody binds to lipoteichoic acid (LTA), or a fragment or portion thereof.

193. The method of embodiment 192, wherein the antibody is pagibaximab (BSYX-A1 10). 194. The method of any of embodiments 152-162, wherein the antibody or the antigen-binding fragment of the antibody binds to Clumping Factor A (ClfA), or a fragment or portion thereof.

195. The method of embodiment 194, wherein the antibody is tefibazumab.

196. The method of embodiment 194, wherein the antibody is Veronate.

197. The method of any of embodiments 152-162, wherein the antibody or the antigen-binding fragment of the antibody binds to ATP -binding cassette (ABC) transporter component GrfA, or a fragment or portion thereof.

198. The method of embodiment 197, wherein the antibody is Aurograb.

199. The method of any of embodiments 152-162, wherein the antibody or the antigen-binding fragment of the antibody binds to poly-N-acetylated glucosamine (PNAG) , or a fragment or portion thereof.

200. The method of embodiment 199, wherein the antibody is SAR279356 (F598).

201. The method of any of embodiments 152-162, wherein the antibody or the antigen-binding fragment of the antibody binds to alpha-toxin (AT), or a fragment or portion thereof.

202. The method of embodiment 201, wherein the antibody is MEDI4893.

203. The method of embodiment 201, wherein the antibody is AR-301.

204. The method of any of embodiments 152-162, wherein the antibody or the antigen-binding fragment of the antibody binds to a bacterial molecule selected from an amidase (Amd) protein or polypeptide, an iron-regulated surface determinant protein A (IsdA) protein or polypeptide, an iron-regulated surface determinant protein B (IsdB) protein or polypeptide, an iron-regulated surface determinant protein H (IsdH) protein or polypeptide, a Clumping Factor A (ClfA) protein or polypeptide, a Clumping Factor B (ClfB) protein or polypeptide, a Fibronectin Binding Protein A (FnbpA) protein or polypeptide, a Staphylococcus Complement Inhibitor (SCIN) protein or polypeptide, a Chemotaxis Inhibitory Protein of Staphylococcus aureus (CHIPS) protein or polypeptide, an alpha-Hemolysin (Hla) protein or polypeptide, an Extracellular Fibrinogen-binding (Efb) protein or polypeptide, S pro-toxin subunit from Staphylococcus (LukS-PV) protein or polypeptide, Ser-Asp dipeptide repeat G from (SdrG) protein or polypeptide, staphylococcal enteroxin B (SEB) protein or polypeptide, N-terminus of the candidal surface adhesin (rAls3p-N) protein or polypeptide, extracellular adherence protein (Eap) protein or polypeptide, Serine aspartate repeat containing protein D (SdrD) protein or polypeptide, Serine aspartate repeat containing protein E (SdrE) protein or polypeptide, staphylococcal antigen A (IsaA) protein or polypeptide, protein A or a polypeptide of protein A, panton-valentine leucocidin (PVL) protein or polypeptide, γ-hemolysin C (HlgC) protein or polypeptide, Ferric

205. The method of embodiment 204, wherein the bacterial molecule is from Staphylococcus.

206. The method of embodiment 204, wherein the bacterial molecule is from Staphylococcus aureus.

207. The method of any of embodiments 152-162, wherein the antibody or the antigen binding fragment of the antibody is selected from Altastaph, Veronate, Aurexis (tefibazumab), pagibaximab (BSYX- A110), Aurograb, SAR279356 (F598), MEDI4893, Salvecin (AR-301, KBSA301), and 514G3 (XBiotech).

208. A method of an embodiment for identifying antibacterial activity of a compound of Formula (I) for a test bacteria, the method comprising contacting the test bacteria with a compound of Formula (I)

Formula (I)

or pharmaceutically acceptable salt or solvate thereof, wherein:

209. The method of embodiment 208, wherein the antibacterial compound of Formula (I) has the structure of Formula (la)

Formula (la)

or pharmaceutically acceptable salt or solvate thereof, wherein:

X¹, X², X³, X⁴, and X⁵ are independently selected from N, CH, and CR⁴;

Y¹, Y², Y³, Y⁴, and Y⁵ are independently selected from N, CH, and CR⁴;

p is 0, 1, 2, 3, 4 or 5.

The method of embodiment 209, wherein the antibacterial compound of Formula (la) has the structure of Formula (lb)

Formula (lb)

or pharmaceutically acceptable salt or solvate thereof, wherein:

optionally be substituted with -F, -OH, and -OMe, and C₃-C₇cycloalkyl;

The method of embodiment 210, wherein the antibacterial compound of Formula (lb) has the structure of avasimibe

or pharmaceutically acceptable salt or solvate thereof. 212. The method of any of embodiments 208-21 1, wherein if the compound of Formula (I) kills or inhibits the test bacteria after contact, the compound of Formula (I) is identified as having antibacterial activity for the test bacteria.

213. The method of embodiment 212, wherein inhibition of the test bacteria comprises (i) reducing growth of the bacteria, (ii) reducing replication of the bacteria, (iii) reducing propagation of the bacteria, (iv) reducing viable bacteria population, or (v) a combination of any of (i)-(iv).

214. The method of any of embodiments 208-213, wherein the antibacterial activity is evaluated by

measuring the minimal inhibitory concentration 50% (MIC50) of the compound of Formula (I) for the test bacteria.

215. The method of embodiment 214, wherein if the MIC50 is less than about 50 μΜ, 40 μΜ, 30 μΜ, 20 μΜ, 10 μΜ, 1 μΜ, 100 ηΜ, 10 ηΜ, 1 ηΜ, 100 ρΜ or 10 ρΜ, the compound of Formula (I) is identified as having antibacterial activity for the test bacteria.

216. The method of any of embodiments 208-215, wherein contacting comprises bringing the test bacteria in proximity to the compound of Formula (I) such that if the compound of Formula (I) has antibacterial activity for the test bacteria, the antibacterial activity is provided.

217. The method of any of embodiments 208-216, wherein contacting comprises combining the compound of Formula (I) with the test bacteria in an in vitro solution.

218. The method of embodiment 217, wherein contacting comprises providing a solution comprising the test bacteria, and adding to the solution the compound of Formula (I).

219. The method of embodiment 217, wherein contacting comprises providing a solution comprising the compound of Formula (I), and adding to the solution the test bacteria.

220. The method of any of embodiments 208-216, wherein contacting comprises providing the compound of Formula (I) on a surface comprising the test bacteria.

221. The method of any of embodiments 208-216, wherein contacting comprises administering the

compound of Formula (I) to a subject infected with the test bacteria.

222. The method of embodiment 221, wherein the compound of Formula (I) is administered orally,

intravenously, subcutaneously or by nasogastric or orogastric intubation.

223. The method of embodiment 221 or embodiment 222, wherein the subject is a human subject or a non- human animal subject.

224. The method of embodiment 223, wherein the non -human animal is a mouse.

225. The method of any of embodiments 208-224, wherein the test bacteria is a Gram -positive bacteria.

226. The method of embodiment 225, wherein the Gram -positive bacteria is selected from the genus

Staphylococcus, Bacillus, Enterococcus , Streptococcus, and Clostridium.

227. The method of embodiment 225, wherein the Gram -positive bacteria is selected from Staphylococcus aureus, Staphylococcus epidermidis, Bacillus subtilis, Enterococcus faecium, Streptococcus pneumonia, Streptococcus pyogenes, and Clostridium difficile.

228. The method of any of embodiments 208-224, wherein the test bacteria is a Gram -negative bacteria. 229. The method of embodiment 228, wherein the Gram-negative bacteria is selected from the genus

Pseudomonas, Escherichia, Haemophilus, Acinetobacter, and Klebsiella.

230. The method of embodiment 228, wherein the Gram-negative bacteria is selected from Pseudomonas aeruginosa, Escherichia coli, Haemophilus influenzae, Acinetobacter baumannii, and Klebsiella pneumonia.

231. The method of any of embodiments 208-230, wherein the test bacteria has resistance to a drug.

232. The method of embodiment 231, wherein the drug is an antibiotic.

233. The method of embodiment 232, wherein the antibiotic is a polymyxin antibiotic.

234. The method of embodiment 233, wherein the polymyxin antibiotic comprises polymyxin B and/or colistin.

235. The method of embodiment 232, wherein the antibiotic is a beta-lactam antibiotic.

236. The method of embodiment 235, wherein the beta-lactam antibiotic comprises penicillin, methicillin, oxacillin, nafcillin, ampicillin, amoxicillin, carbenicillin or a combination thereof.

237. The method of embodiment 232, wherein the antibiotic is a fluoroquinolone antibiotic.

238. The method of embodiment 232, wherein the antibiotic is a cephalosporin antibiotic.

239. The method of embodiment 232, wherein the antibiotic is a carbapenem antibiotic.

240. The method of embodiment 232, wherein the antibiotic is a cephalosporin antibiotic.

241. The method of embodiment 232, wherein the antibiotic comprises methicillin, vancomycin,

erythromycin, doxycycline, tetracycline, linezolid, clindamycin, ceftriazone, or a combination thereof.

242. The method of any of embodiments 208-241, further comprising contacting the bacteria with an

antibacterial compound.

243. The method of embodiment 242, wherein the antibacterial compound comprises an aminoglycoside.

244. The method of embodiment 243, wherein the aminoglycoside comprises kanamycin, amikacin,

245. A method of treating a bacterial infection in an individual in need thereof, the method comprising administering to the individual a compound identified as having antibacterial activity as in any of embodiments 208-244.

246. The method of embodiment 208, wherein the test bacteria is S. aureus.

247. The method of any of embodiments 208-246, further comprising contacting the test bacteria with an antibody or an antigen-binding fragment of the antibody.

248. The method of embodiment 247, wherein the test bacteria is contacted with the antibody or the

antigen-binding fragment of the antibody prior to contacting the test bacteria with the antibacterial compound of Formula (I). 249. The method of embodiment 247, wherein the test bacteria is contacted with the antibody or the antigen-binding fragment of the antibody after contacting the test bacteria with the antibacterial compound of Formula (I).

250. The method of embodiment 247, wherein the antibody or the antigen-binding fragment of the

antibody contacts the test bacteria separately from the antibacterial compound of Formula (I).

251. The method of any of embodiments 247-250, wherein the antibody or the antigen-binding fragment of the antibody prevents infection, growth, or propagation of the test bacteria.

252. The method of any of embodiments 247-251, wherein the antibody or the antigen-binding fragment of the antibody promotes lysis of the test bacteria.

253. The method of any of embodiments 247-252, wherein the antibody or the antigen-binding fragment of the antibody binds to a peptide or portion thereof from a bacteria selected from Staphylococcus, Bacillus, Enter ococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, and Klebsiella.

254. The method of embodiment 253, wherein the bacteria to which the antibody or the antigen-binding fragment of the antibody binds is drug-resistant.

255. The method of embodiment 254, wherein the drug-resistant bacteria is resistant to methicillin.

256. The method of any of embodiments 247-255, wherein the antibody is a monoclonal antibody.

257. The method of any of embodiments 247-256, wherein the antibody is humanized.

258. The method of any of embodiments 247-257, wherein the antibody or the antigen-binding fragment of the antibody binds to an autolysin or fragment thereof.

259. The method of embodiment 258, wherein the autolysin is from a bacteria selected from

260. The method of embodiment 259, wherein the autolysin is from Stapylococcus .

261. The method of any of embodiments 258-260, wherein the antibody or the antigen-binding fragment of the antibody at least partially or wholly binds to the glucosaminidase subunit of the autolysin, or a fragment of the glucosaminidase subunit.

262. The method of embodiment 261, wherein the glucosaminidase comprises the sequence of SEQ ID NO:

1.

263. The method of embodiment 261 or embodiment 262, wherein the glucosaminidase is a

Staphylococcus aureus glucosaminidase.

264. The method of any of embodiments 261-263, wherein the antibody or the antigen-binding fragment of the antibody binds to an epitope at least partially positioned within the glucosaminidase R3 domain.

265. The method of any of embodiments 261-263, wherein the antibody or the antigen-binding fragment of the antibody binds to an epitope within the glucosaminidase catalytic domain.

266. The method of any of embodiments 261-265, wherein the antibody or the antigen-binding fragment of the antibody inhibits activity of the glucosaminidase. 267. The method of any of embodiments 261-266, wherein the antibody or the antigen-binding fragment of the antibody comprises a variable domain sequence at least 80%, 85%, 90%, 95%, or 99%

homologous to a sequence selected from SEQ ID NO: 2-13.

268. The method of any of embodiments 261-267, wherein the antibody or the antigen-binding fragment of the antibody comprises one or more CDRs selected from SEQ ID NOS: 2-13.

269. The method of any of embodiments 261-268, wherein the antibody or the antigen-binding fragment of the antibody comprises the sequences of amino acid residues 31 -35, 50-66, and 99-1 10 of SEQ ID NO: 6 and/or the sequence of amino acid residues 24-31, 50-56, and 89-95 of SEQ ID NO: 1 1.

270. The method of any of embodiments 247-257, wherein the antibody or the antigen-binding fragment of the antibody binds to a bacterial autolysin N-acetylmuramoyl-L-alanine amidase catalytic domain or a fragment or portion thereof.

271. The method of embodiment 270, wherein the bacterial autolysin N-acetylmuramoyl-L-alanine

amidase catalytic domain is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus , Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

272. The method of any of embodiments 247-257, wherein the antibody or the antigen-binding fragment of the antibody binds to a bacterial cell wall binding domain, or a fragment or portion thereof.

273. The method of embodiment 272, wherein the bacterial cell wall binding domain is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

274. The method of any of embodiments 247-257, wherein the antibody or the antigen-binding fragment of the antibody binds to a bacterial cell surface-associated antigen, or a fragment or portion thereof.

275. The method of embodiment 274, wherein the bacterial cell surface-associated antigen is from a

bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium,

276. The method of any of embodiments 247-257, wherein the antibody or the antigen-binding fragment of the antibody binds to a bacterial exotoxin, or a fragment or portion thereof.

277. The method of embodiment 276, wherein the bacterial exotoxin is from a bacteria selected from

278. The method of any of embodiments 247-257, wherein the antibody or the antigen-binding fragment of the antibody binds to a bacterial protease, or a fragment or portion thereof.

279. The method of embodiment 278, wherein the bacterial protease is V8 protease, a member of the

glutamyl endopeptidase I family of Staphylococcus aureus V8 strain (GluV8), or a fragment or portion thereof. 280. The method of embodiment 278, wherein the bacterial protease is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus , Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

281. The method of any of embodiments 247-257, wherein the antibody or the antigen-binding fragment of the antibody binds to a bacterial leucocidin, or a fragment or portion thereof.

282. The method of embodiment 281, wherein the bacterial leucocidin is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

283. The method of any of embodiments 247-257, wherein the antibody or the antigen-binding fragment of the antibody binds to a bacterial adhesin, or a fragment or portion thereof.

284. The method of embodiment 283, wherein the bacterial adhesin is from a bacteria selected from

285. The method of embodiment 283 or embodiment 284, wherein the bacterial adhesin is a surface-bound adhesin that promotes host colonization.

286. The method of any of embodiments 247-257, wherein the antibody or the antigen-binding fragment of the antibody binds to a cell surface adhesin that interacts with an extracellular matrix component (microbial surface component recognizing adhesive matrix molecules or MSCRAMMs), or a fragment or portion thereof.

287. The method of any of embodiments 247-257, wherein the antibody or the antigen-binding fragment of the antibody binds to lipoteichoic acid (LTA), or a fragment or portion thereof.

288. The method of embodiment 287, wherein the antibody is pagibaximab (BSYX-A1 10).

289. The method of any of embodiments 247-257, wherein the antibody or the antigen-binding fragment of the antibody binds to Clumping Factor A (ClfA), or a fragment or portion thereof.

290. The method of embodiment 289, wherein the antibody is tefibazumab.

291. The method of embodiment 289, wherein the antibody is Veronate.

292. The method of any of embodiments 247-257, wherein the antibody or the antigen-binding fragment of the antibody binds to ATP -binding cassette (ABC) transporter component GrfA, or a fragment or portion thereof.

293. The method of embodiment 292, wherein the antibody is Aurograb.

294. The method of any of embodiments 247-257, wherein the antibody or the antigen-binding fragment of the antibody binds to poly-N-acetylated glucosamine (PNAG) , or a fragment or portion thereof.

295. The method of embodiment 294, wherein the antibody is SAR279356 (F598).

296. The method of any of embodiments 247-257, wherein the antibody or the antigen-binding fragment of the antibody binds to alpha-toxin (AT), or a fragment or portion thereof.

297. The method of embodiment 296, wherein the antibody is MEDI4893.

298. The method of embodiment 296, wherein the antibody is AR-301. 299. The method of any of embodiments 247-257, wherein the antibody or the antigen-binding fragment of the antibody binds to a bacterial molecule selected from an amidase (Amd) protein or polypeptide, an iron-regulated surface determinant protein A (IsdA) protein or polypeptide, an iron-regulated surface determinant protein B (IsdB) protein or polypeptide, an iron-regulated surface determinant protein H (IsdH) protein or polypeptide, a Clumping Factor A (ClfA) protein or polypeptide, a Clumping Factor B (ClfB) protein or polypeptide, a Fibronectin Binding Protein A (FnbpA) protein or polypeptide, a Staphylococcus Complement Inhibitor (SCIN) protein or polypeptide, a Chemotaxis Inhibitory Protein of Staphylococcus aureus (CHIPS) protein or polypeptide, an alpha-Hemolysin (Hla) protein or polypeptide, an Extracellular Fibrinogen-binding (Efb) protein or polypeptide, S pro-toxin subunit from Staphylococcus (LukS-PV) protein or polypeptide, Ser-Asp dipeptide repeat G from (SdrG) protein or polypeptide, staphylococcal enteroxin B (SEB) protein or polypeptide, N-terminus of the candidal surface adhesin (rAls3p-N) protein or polypeptide, extracellular adherence protein (Eap) protein or polypeptide, Serine aspartate repeat containing protein D (SdrD) protein or polypeptide, Serine aspartate repeat containing protein E (SdrE) protein or polypeptide, staphylococcal antigen A (IsaA) protein or polypeptide, protein A or a polypeptide of protein A, panton-valentine leucocidin (PVL) protein or polypeptide, γ-hemolysin C (HlgC) protein or polypeptide, Ferric

300. The method of embodiment 299, wherein the bacterial molecule is from Staphylococcus.

301. The method of embodiment 299, wherein the bacterial molecule is from Staphylococcus aureus.

302. The method of any of embodiments 247-257, wherein the antibody or the antigen binding fragment of the antibody is selected from Altastaph, Veronate, Aurexis (tefibazumab), pagibaximab (BSYX- A110), Aurograb, SAR279356 (F598), MEDI4893, Salvecin (AR-301, KBSA301), and 514G3 (XBiotech).

303. An embodiment of a combination comprising an antibacterial compound and a compound of Formula

(I)

Formula (I)

or pharmaceutically acceptable salt or solvate thereof, wherein:

R¹ and Pv³ are independently selected from substituted or unsubstituted Ci-Ci₀alkyl, substituted or unsubstituted C₃-Ci₀cycloalkyl, substituted or unsubstituted C₂-Ci₀heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, wherein if R¹ and R³ are substituted then R¹ and R³ are independently substituted with one or more R⁴ groups; each R⁴ is independently selected from D, -OR⁵, -SR⁵, -F, -CI, -Br, -I, -C(0)R⁵, -C0₂R⁵, -CN, - N0₂, -N(R⁶)(R⁷), substituted or unsubstituted Ci-C₇alkyl, substituted or unsubstituted C₃- C₇cycloalkyl, substituted or unsubstituted C₂-C₆heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

304. The combination of embodiment 303, wherein the compound of Formula (I) has the structure of Formula (la)

Formula (la)

or pharmaceutically acceptable salt or solvate thereof, wherein:

p is 0, 1, 2, 3, 4 or 5.

305. The combination of embodiment 304, wherein the compound of Formula (la) has the structure of Formula (lb)

Formula (lb)

or pharmaceutically acceptable salt or solvate thereof, wherein:

optionally be substituted with -F, -OH, and -OMe, and C₃-C₇cycloalkyl;

The combination of embodiment 305, wherein the compound of Formula (lb) has the structure of avasimibe

or pharmaceutically acceptable salt or solvate thereof.

307. The combination of any of embodiments 303-306, wherein the antibacterial compound comprises an aminoglycoside.

308. The combination of embodiment 307, wherein the aminoglycoside comprises kanamycin, amikacin, apramycin, arbekacin, astromicin, bekanamycin, capreomycin, dibekacin, dihydrostreptomycin, elsamitrucin, fosfomycin, tobramycin, g418, gentamicin, hygromycin b, isepamicin, kanamycin, kasugamycin, legonmycin, lividomycin, micronomicin, neamine, neomycin, netilmicin, nourseothricin, paromomycin, plazomicin, ribostamycin, sisomicin, streptoduocin, streptomycin, tobramycin, totomycin, verdamicin or a combination thereof.

309. The combination of any of embodiments 303-308, wherein the antibacterial compound and the compound of Formula (I) are formulated in a composition.

310. The combination of any of embodiments 303-308, wherein the antibacterial compound and the compound of Formula (I) are formulated in separate compositions. 311. The combination of any of embodiments 303-310, wherein the antibacterial compound is formulated for oral administration, intravenous administration or administration by nasogastric or orogastric intubation.

312. The combination of any of embodiments 303-311, wherein the compound of Formula (I) is

formulated for oral administration, intravenous administration or administration by nasogastric or orogastric intubation.

313. The combination of any of embodiments 303-312, wherein the antibacterial compound is formulated in a tablet, pill, gel-cap, or liquid.

314. The combination of any of embodiments 303-313, wherein the compound of Formula (I) is

formulated in a tablet, pill, gel-cap, or liquid.

315. A method of treating a bacterial infection in a subject in need thereof, the method comprising

administering to the subject the combination of any of embodiments 303-314.

316. The combination of any of embodiments 303-315, further comprising an antibody or an antigen- binding fragment of the antibody.

317. The combination of embodiment 316, wherein the antibody or the antigen -binding fragment of the antibody is formulated in a composition with the antibacterial compound of Formula (I).

318. The combination of embodiment 316, wherein the antibody or the antigen -binding fragment of the antibody is not formulated in a composition with the antibacterial compound of Formula (I).

319. The combination of any of embodiments 316-318, wherein the antibody or the antigen-binding fragment of the antibody binds to a peptide or portion thereof from a bacteria selected from

320. The combination of embodiment 319, wherein the bacteria to which the antibody or the antigen- binding fragment of the antibody binds is drug-resistant.

321. The combination of embodiment 320, wherein the drug -resistant bacteria is resistant to methicillin.

322. The combination of any of embodiments 316-321, wherein the antibody is a monoclonal antibody.

323. The combination of any of embodiments 316-322, wherein the antibody is humanized.

324. The combination of any of embodiments 316-323, wherein the antibody or the antigen-binding fragment of the antibody binds to an autolysin or fragment thereof.

325. The combination of embodiment 324, wherein the autolysin is from a bacteria selected from

Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, and Klebsiella.

326. The combination of embodiment 325, wherein the autolysin is from Stapylococcus .

327. The combination of any of embodiments 324-326, wherein the antibody or the antigen-binding fragment of the antibody at least partially or wholly binds to the glucosaminidase subunit of the autolysin, or a fragment of the glucosaminidase subunit. 328. The combination of embodiment 327, wherein the glucosaminidase comprises the sequence of SEQ ID NO: 1.

329. The combination of embodiment 327 or embodiment 328, wherein the glucosaminidase is a

Staphylococcus aureus glucosaminidase.

330. The combination of any of embodiments 327-329, wherein the antibody or the antigen-binding

fragment of the antibody binds to an epitope at least partially positioned within the glucosaminidase R3 domain.

331. The combination of any of embodiments 327-329, wherein the antibody or the antigen-binding

332. The combination of any of embodiments 327-331, wherein the antibody or the antigen-binding

fragment of the antibody inhibits activity of the glucosaminidase.

333. The combination of any of embodiments 327-332, wherein the antibody or the antigen-binding

fragment of the antibody comprises a variable domain sequence at least 80%, 85%, 90%, 95%, or 99% homologous to a sequence selected from SEQ ID NO: 2-13.

334. The combination of any of embodiments 327-333, wherein the antibody or the antigen-binding

fragment of the antibody comprises one or more CDRs selected from SEQ ID NOS: 2-13.

335. The combination of any of embodiments 327-334, wherein the antibody or the antigen-binding

fragment of the antibody comprises the sequences of amino acid residues 31 -35, 50-66, and 99-1 10 of SEQ ID NO: 6 and/or the sequence of amino acid residues 24-31, 50-56, and 89-95 of SEQ ID NO: 1 1.

336. The combination of any of embodiments 316-323, wherein the antibody or the antigen-binding

fragment of the antibody binds to a bacterial autolysin N-acetylmuramoyl-L-alanine amidase catalytic domain or a fragment or portion thereof.

337. The combination of embodiment 336, wherein the bacterial autolysin N-acetylmuramoyl-L-alanine amidase catalytic domain is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus , Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

338. The combination of any of embodiments 316-323, wherein the antibody or the antigen-binding

fragment of the antibody binds to a bacterial cell wall binding domain, or a fragment or portion thereof.

339. The combination of embodiment 338, wherein the bacterial cell wall binding domain is from a

340. The combination of any of embodiments 316-323, wherein the antibody or the antigen-binding

fragment of the antibody binds to a bacterial cell surface -associated antigen, or a fragment or portion thereof. 341. The combination of embodiment 340, wherein the bacterial cell surface -associated antigen is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus , Streptococcus, Clostridium,

342. The combination of any of embodiments 316-323, wherein the antibody or the antigen-binding

fragment of the antibody binds to a bacterial exotoxin, or a fragment or portion thereof.

343. The combination of embodiment 342, wherein the bacterial exotoxin is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

344. The combination of any of embodiments 316-323, wherein the antibody or the antigen-binding

fragment of the antibody binds to a bacterial protease, or a fragment or portion thereof.

345. The combination of embodiment 344, wherein the bacterial protease is V8 protease, a member of the glutamyl endopeptidase I family of Staphylococcus aureus V8 strain (GluV8), or a fragment or portion thereof.

346. The combination of embodiment 344, wherein the bacterial protease is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

347. The combination of any of embodiments 316-323, wherein the antibody or the antigen-binding

fragment of the antibody binds to a bacterial leucocidin, or a fragment or portion thereof.

348. The combination of embodiment 347, wherein the bacterial leucocidin is from a bacteria selected

from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

349. The combination of any of embodiments 316-323, wherein the antibody or the antigen-binding

fragment of the antibody binds to a bacterial adhesin, or a fragment or portion thereof.

350. The combination of embodiment 349, wherein the bacterial adhesin is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

351. The combination of embodiment 349 or embodiment 350, wherein the bacterial adhesin is a surface- bound adhesin that promotes host colonization.

352. The combination of any of embodiments 316-323, wherein the antibody or the antigen-binding

fragment of the antibody binds to a cell surface adhesin that interacts with an extracellular matrix component (microbial surface component recognizing adhesive matrix molecules or MSCRAMMs), or a fragment or portion thereof.

353. The combination of any of embodiments 316-323, wherein the antibody or the antigen-binding

fragment of the antibody binds to lipoteichoic acid (LTA), or a fragment or portion thereof.

354. The combination of embodiment 353, wherein the antibody is pagibaximab (BSYX-A1 10).

355. The combination of any of embodiments 316-323, wherein the antibody or the antigen-binding

fragment of the antibody binds to Clumping Factor A (ClfA), or a fragment or portion thereof. 356. The combination of embodiment 355, wherein the antibody is tefibazumab.

357. The combination of embodiment 355, wherein the antibody is Veronate.

358. The combination of any of embodiments 316-323, wherein the antibody or the antigen-binding

fragment of the antibody binds to ATP -binding cassette (ABC) transporter component GrfA, or a fragment or portion thereof.

359. The combination of embodiment 358, wherein the antibody is Aurograb.

360. The combination of any of embodiments 316-323, wherein the antibody or the antigen-binding

fragment of the antibody binds to poly-N-acetylated glucosamine (PNAG) , or a fragment or portion thereof.

361. The combination of embodiment 360, wherein the antibody is SAR279356 (F598).

362. The combination of any of embodiments 316-323, wherein the antibody or the antigen-binding

fragment of the antibody binds to alpha-toxin (AT), or a fragment or portion thereof.

363. The combination of embodiment 362, wherein the antibody is MEDI4893.

364. The combination of embodiment 362, wherein the antibody is AR-301.

365. The combination of any of embodiments 316-323, wherein the antibody or the antigen-binding

fragment of the antibody binds to a bacterial molecule selected from an amidase (Amd) protein or polypeptide, an iron-regulated surface determinant protein A (IsdA) protein or polypeptide, an iron- regulated surface determinant protein B (IsdB) protein or polypeptide, an iron-regulated surface determinant protein H (IsdH) protein or polypeptide, a Clumping Factor A (ClfA) protein or polypeptide, a Clumping Factor B (ClfB) protein or polypeptide, a Fibronectin Binding Protein A (FnbpA) protein or polypeptide, a Staphylococcus Complement Inhibitor (SCIN) protein or polypeptide, a Chemotaxis Inhibitory Protein of Staphylococcus aureus (CHIPS) protein or polypeptide, an alpha-Hemolysin (Hla) protein or polypeptide, an Extracellular Fibrinogen-binding (Efb) protein or polypeptide, S pro-toxin subunit from Staphylococcus (LukS-PV) protein or polypeptide, Ser-Asp dipeptide repeat G from (SdrG) protein or polypeptide, staphylococcal enteroxin B (SEB) protein or polypeptide, N-terminus of the candidal surface adhesin (rAls3p-N) protein or polypeptide, extracellular adherence protein (Eap) protein or polypeptide, Serine aspartate repeat containing protein D (SdrD) protein or polypeptide, Serine aspartate repeat containing protein E (SdrE) protein or polypeptide, staphylococcal antigen A (IsaA) protein or polypeptide, protein A or a polypeptide of protein A, panton-valentine leucocidin (PVL) protein or polypeptide, γ-hemolysin C (HlgC) protein or polypeptide, Ferric hydroxamate -binding lipoprotein (FhuD2) protein or polypeptide, capsular polysaccharide type 5, capsular polysaccharide type 8; or a combination, fragment and/or portion thereof.

366. The combination of embodiment 365, wherein the bacterial molecule is from Staphylococcus .

367. The combination of embodiment 365, wherein the bacterial molecule is from Staphylococcus aureus.

368. The combination of any of embodiments 316-323, wherein the antibody or the antigen binding

fragment of the antibody is selected from Altastaph, Veronate, Aurexis (tefibazumab), pagibaximab (BSYX-A110), Aurograb, SAR279356 (F598), MEDI4893, Salvecin (AR-301, KBSA301), and 514G3 (XBiotech).

369. An embodiment of a combination comprising an antibody or an antigen binding fragment of the

antibody, and a compound of Formula (I)

Formula (I)

or pharmaceutically acceptable salt or solvate thereof, wherein:

370. The combination of embodiment 369, wherein the compound of Formula (I) has the structure of

Formula (la)

Formula (la)

or pharmaceutically acceptable salt or solvate thereof, wherein:

X¹, X², X³, X⁴, and X⁵ are independently selected from N, CH, and CR⁴;

Y¹, Y², Y³, Y⁴, and Y⁵ are independently selected from N, CH, and CR⁴;

p is 0, 1, 2, 3, 4 or 5.

The combination of embodiment 370, wherein the compound of Formula (la) has the structure of Formula (lb)

Formula (lb)

or pharmaceutically acceptable salt or solvate thereof, wherein:

optionally be substituted with -F, -OH, and -OMe, and C₃-C₇cycloalkyl;

The combination of embodiment 371 , wherein the compound of Formula (lb) has the structure of avasimibe

or pharmaceutically acceptable salt or solvate thereof.

The combination of any of embodiments 369-372, wherein the antibody or an antigen binding fragment of the antibody and the compound of Formula (I) are formulated in a composition. 374. The combination of any of embodiments 369-372, wherein the antibody or an antigen binding fragment of the antibody and the compound of Formula (I) are formulated in separate compositions.

375. The combination of any of embodiments 369-374, wherein the antibody or an antigen binding

fragment of the antibody is formulated for oral administration, intravenous administration or administration by nasogastric or orogastric intubation.

376. The combination of any of embodiments 369-375, wherein the compound of Formula (I) is

377. The combination of any of embodiments 369-374, wherein the antibody or an antigen binding

fragment of the antibody is formulated in a tablet, pill, gel-cap, or liquid.

378. The combination of any of embodiments 369-374 and 377, wherein the compound of Formula (I) is formulated in a tablet, pill, gel-cap, or liquid.

379. The combination of any of embodiments 369-378, wherein the antibody or the antigen-binding fragment of the antibody binds to a peptide or portion thereof from a bacteria selected from

380. The combination of embodiment 379, wherein the bacteria to which the antibody or the antigen- binding fragment of the antibody binds is drug-resistant.

381. The combination of embodiment 380, wherein the drug -resistant bacteria is resistant to methicillin.

382. The combination of any of embodiments 369-381, wherein the antibody is a monoclonal antibody.

383. The combination of any of embodiments 369-382, wherein the antibody is humanized.

384. The combination of any of embodiments 369-383, wherein the antibody or the antigen-binding fragment of the antibody binds to an autolysin or fragment thereof.

385. The combination of embodiment 384, wherein the autolysin is from a bacteria selected from

386. The combination of embodiment 385, wherein the autolysin is from Stapylococcus .

387. The combination of any of embodiments 369-383, wherein the antibody or the antigen-binding fragment of the antibody at least partially or wholly binds to the glucosaminidase subunit of the autolysin, or a fragment of the glucosaminidase subunit.

388. The combination of embodiment 387, wherein the glucosaminidase comprises the sequence of SEQ ID NO: 1.

389. The combination of embodiment 387 or embodiment 388, wherein the glucosaminidase is a

Staphylococcus aureus glucosaminidase.

390. The combination of any of embodiments 387-389, wherein the antibody or the antigen-binding fragment of the antibody binds to an epitope at least partially positioned within the glucosaminidase R3 domain. 391. The combination of any of embodiments 387-390, wherein the antibody or the antigen-binding fragment of the antibody binds to an epitope within the glucosaminidase catalytic domain.

392. The combination of any of embodiments 387-391, wherein the antibody or the antigen-binding

fragment of the antibody inhibits activity of the glucosaminidase.

393. The combination of any of embodiments 369-392, wherein the antibody or the antigen-binding

394. The combination of any of embodiments 369-393, wherein the antibody or the antigen-binding

395. The combination of any of embodiments 369-394, wherein the antibody or the antigen-binding

396. The combination of any of embodiments 369-383, wherein the antibody or the antigen-binding

397. The combination of embodiment 396, wherein the bacterial autolysin N-acetylmuramoyl-L-alanine amidase catalytic domain is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus , Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

398. The combination of any of embodiments 369-383, wherein the antibody or the antigen-binding

399. The combination of embodiment 398, wherein the bacterial cell wall binding domain is from a

400. The combination of any of embodiments 369-383, wherein the antibody or the antigen-binding

fragment of the antibody binds to a bacterial cell surface -associated antigen, or a fragment or portion thereof.

401. The combination of embodiment 400, wherein the bacterial cell surface -associated antigen is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium,

402. The combination of any of embodiments 369-383, wherein the antibody or the antigen-binding

403. The combination of embodiment 402, wherein the bacterial exotoxin is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof. 404. The combination of any of embodiments 369-383, wherein the antibody or the antigen-binding fragment of the antibody binds to a bacterial protease, or a fragment or portion thereof.

405. The combination of embodiment 404, wherein the bacterial protease is V8 protease, a member of the glutamyl endopeptidase I family of Staphylococcus aureus V8 strain (GluV8), or a fragment or portion thereof.

406. The combination of embodiment 404, wherein the bacterial protease is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus , Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

407. The combination of any of embodiments 369-383, wherein the antibody or the antigen-binding

408. The combination of embodiment 407, wherein the bacterial leucocidin is from a bacteria selected

409. The combination of any of embodiments 369-383, wherein the antibody or the antigen-binding

410. The combination of embodiment 409, wherein the bacterial adhesin is from a bacteria selected from Staphylococcus, Bacillus, Enterococcus, Streptococcus, Clostridium, Pseudomonas, Escherichia, Haemophilus, Acinetobacter, Klebsiella, and a combination thereof.

41 1. The combination of embodiment 409 or embodiment 410, wherein the bacterial adhesin is a surface- bound adhesin that promotes host colonization.

412. The combination of any of embodiments 369-383, wherein the antibody or the antigen-binding

413. The combination of any of embodiments 369-383, wherein the antibody or the antigen-binding

414. The combination of embodiment 413, wherein the antibody is pagibaximab (BSYX-A1 10).

415. The combination of any of embodiments 369-383, wherein the antibody or the antigen-binding

fragment of the antibody binds to Clumping Factor A (ClfA), or a fragment or portion thereof.

416. The combination of embodiment 415, wherein the antibody is tefibazumab.

417. The combination of embodiment 415, wherein the antibody is Veronate.

418. The combination of any of embodiments 369-383, wherein the antibody or the antigen-binding

419. The combination of embodiment 418, wherein the antibody is Aurograb. 420. The combination of any of embodiments 369-383, wherein the antibody or the antigen-binding fragment of the antibody binds to poly-N-acetylated glucosamine (PNAG) , or a fragment or portion thereof.

421. The combination of embodiment 420, wherein the antibody is SAR279356 (F598).

422. The combination of any of embodiments 369-383, wherein the antibody or the antigen-binding

423. The combination of embodiment 422, wherein the antibody is MEDI4893.

424. The combination of embodiment 422, wherein the antibody is AR-301.

425. The combination of any of embodiments 369-383, wherein the antibody or the antigen-binding

426. The combination of embodiment 425, wherein the bacterial molecule is from Staphylococcus .

427. The combination of embodiment 425, wherein the bacterial molecule is from Staphylococcus aureus.

428. The combination of any of embodiments 369-383, wherein the antibody or the antigen binding

429. A method of treating a bacterial infection in a subject in need thereof, the method comprising

administering to the subject the combination of any of embodiments 369-429.

430. The method of any of embodiments 57-62, wherein the antibody or the antigen-binding fragment of the antibody comprises a variable domain and/or one or more CDRs from SEQ ID NOS: 14-23. 431. The method of any of embodiments 152-162, wherein the antibody or the antigen-binding fragment of the antibody comprises a variable domain and/or one or more CDRs from SEQ ID NOS: 14-23.

432. The method of any of embodiments 247-257, wherein the antibody or the antigen-binding fragment of the antibody comprises a variable domain and/or one or more CDRs from SEQ ID NOS: 14-23.

433. The combination of any of embodiments 316-323, wherein the antibody or the antigen-binding

fragment of the antibody comprises a variable domain and/or one or more CDRs from SEQ ID NOS: 14-23.

434. The combination of any of embodiments 369-383, wherein the antibody or the antigen-binding

Table 1. Sequence Listing

any amino acid

10 Variable domain DIVMTQSHKFMSTSVGD VSITCKASQDVSTAVAWYQQKPGQSPKLLIYWTST HT

GVPDRFTGSGSGTDFTLTISSVQAKDLALYYCQQHYTTPYTFGGGTKLEIK

11 Variable domain DIVLTQSPATLSVTPGDSVSLSCRASQSISNNLHWYQQKSHESPRLLIEYASRSISGIPSR

FSGGGSGTDFTLSINSVESEDFGLYFCQQSNSWPLTFGAGTKLELK

12 Variable domain QVQLQQPGAE LVGPGTSVKL SCKSSGYTFT KYWM HWLKQR PGQGLEWIGV

IDPSDSYTNY NQ.KFKGKATL TVDTSSSTAY LQLSSLTSED SAVYYCANYY

GSYYDVMDFW GQGTSVTVSS

13 Variable domain DVQITQSPSY LAASPGETIT INCRASKSIS KYLAWYQEKP GKTNKLLICF

GSTLQSGTPS RFSGSGSGTD FTLTISSLEP EDFATYYCQQ HNEYPLTFGA GTKLELKR

14 Variable domain EVQLLESGGGLVQPGGSLRLSCAASGFTFSPYM MQWVRQAPGKGLEWVSSIWPSG

GKTYYADSVKGRFTISRDNSKNTLYLQM NSLRAEDTAVYYCARVRRGGATDYWGQG TLVTVSS

15 Variable domain DIQMTQSPATLSVSPGERATLSCRASQSVSSNLGWYQQKPGQAPRLLIYGASTRATGI

PTRFSGSGSGTEFTLTISSLQSEDFATYYCQQYQNWPLLTFGGGTKVEIK

16 Variable domain EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYYMWWVRQAPGKGLEWVSVIGPSG

GPTQYADSVKGRFTISRDNSKNTLYLQM NSLRAEDTAVYYCARWGGRYSVFETWGQ

GTMVTVSS

17 Variable domain DIQMTQSPATLSVSPGGRATLSCRASQSVRKNVAWYQQKPGQPPRLLIYGASTRAT

GVPARFSGSGSGTEFTLTISRMQPEDFVVYHCQQYSSWPAFGQGTMVEIN

18 Variable domain EVQLLESGGGLVQPGGSLRLSCAASGFTFSRYFMGWVRQAPGKGLEWVSSIYSSGGY

TSYADSVKGRFTISRDNSKNTLYLQM NSLRAEDTAVYYCARRWRDGTFDYWGQGTL VTVSS

19 Variable domain DIQMTQSPSSLSASIGDRVTISCRASQSVREYLNWYQQKPGKAPKLLIFAASSLQSGVP

SRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTRFTFGPGTKVDIK

20 Variable domain QVQLQQSGAEVKKPGSSVKVSCKASGGTFSSYPISWVRQAPGQGLEWMGKIIPIFGT

TNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAIYYCASPNRPYNIGWHYYFDYWG KGTLVTVSS

21 Variable domain QSVLTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLM IYEGSKRP

SGVSNRFSGSRSGNTASLTISGLQAEDEADYYCSSYTTRSTRVFGGGTKLTVL

22 Variable domain EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGG

STYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDQDEGRANNWWIPP GGRWGQGTM VTVSS

23 Variable domain SSELTQDPTLSVALGQTVRITCQGDSLRRSFASWYQKKPGQAPVLLIYGQNKRPAGIP

DRFSGSRSGNSASLTITGAQAEDEADYYCNSRDARLNPYILFGGGTKLTVL

EXAMPLES

Example 1: Antibacterial activity of avasimibe

[00274] The antibacterial activity of avasimibe (FIG. 1) was characterized by determining the minimal inhibitory concentration 50 (MIC₅₀) of avasimibe for inhibition of growth of various bacteria.

[00275] Chemicals

[00276] Compounds to be tested were dissolved and two-fold serial diluted in sterile dimethylsulfoxide (DMSO) to achieve concentrations from 5 mM to 0.0098 mM. Compound stock solutions were stored at -20 °C until use.

[00277] Bacteria [00278] Bacteria tested in this experiment include Staphylococcus aureus NCTC8325, Methicillin-resistant Staphylococcus aureus USA300 (ATCC BAA-1717), Methicillin-resistant Staphylococcus aureus USA200 (ATCC BAA-1720), Bacillus subtilis strain 168, Pseudomonas aeruginosa strain PA01, and Escherichia coli K-12 MG1655. Bacteria that will be tested using similar experimental methods include Staphylococcus aureus Smith ATCC 13709, Methicillin-resistant Staphylococcus aureus USA100 NRS690, Methicillin- resistant Staphylococcus aureus USA100 NRS710, Methicillin-resistant Staphylococcus aureus USA200 NRS651, Methicillin-resistant Staphylococcus aureus US A300 NRS659, Methicillin-resistant Staphylococcus aureus USA300 NRS687, Methicillin-resistant Staphylococcus aureus USA300 NRS702, Methicillin-resistant Staphylococcus aureus USA300 NRS739, Methicillin-resistant Staphylococcus aureus USA400 NRS 123, Methicillin-resistant Staphylococcus aureus USA600 NRS22, Glycopeptide-intermediate Staphylococcus aureus NRS26, Glycopeptide-intermediate Staphylococcus aureus NRS29, Staphylococcus epidermidis RP62A ATCC 35984, vancomycin-resistant Enterococcus faecium strain 752, vancomycin-resistant

Klebsiella pneumonia 82-3632A.

[00279] Bacteria culture

[00280] Bacterial isolates were maintained in Tryptic soy broth (TSB), and subcultured in Mueller Hinton Broth (MHB) at 37°C overnight with constant shaking at 200rpm before the antimicrobial susceptibility assay.

[00281JM/C of avasimibe for bacteria growth inhibition

[00282] MICs were determined by broth microdilution method following the guidelines of the CLSI in clear- bottom 384-well plates (Greiner). Briefly, overnight bacterial cultures were diluted 1 : 1000 with fresh MHB medium and further cultured in 37°C incubator for 4 hours to reach mid-logarithmic grow phase. Bacterial cultures were then adjusted to approximately 1X10⁵ CFU/mL with fresh MHB medium as a bacterial suspension. 0.5 aliquots of 2-fold serial dilution of each compound in DMSO solution were transferred into each row on the 384-well plates, and 49.5 of bacterial suspension prepared as described above were seeded into each well. 0.5 of DMSO was used as negative control. The 384-well plates were incubated at 37 °C for 16 hours, and bacterial growth was recorded by OD₆₀o_nm measurement through a PHERAstar FS HTS plate reader (BMG LABTECH). MIC values were defined as the lowest concentration of the compound that completely inhibited the visible growth. MIC₅₀ values were defined as the concentration of compound at which 50% of the bacteria growth were inhibited compared to the DMSO control group.

[00283] Avasimibe exhibited potent antimicrobial activity against both wild type Staphylococcus aureus strain NCTC8325 and the clinical derived Methicillin-resistant Staphylococcus aureus wild-type, MRSA strain 252, and MRSA USA300 (ATCC BAA-1717) isolates, with MIC₅₀s of 0.74 uM, 0.88 uM and 0.79 uM

respectively, which is comparable to the anti-MRSA drug Vancomycin. FIG. 2 shows the percent inhibition of S. aureus strain NCTC8325, and Methicillin-resistant Staphylococcus aureus USA200 (ATCC BAA-1720) and USA300 (ATCC BAA- 1717) isolates with concentration of avasimibe. Avasimibe was further tested against different Gram -positive (Bacillus subtilis strain 168) bacteria species to evaluate its specificity.

Avasimibe showed slightly lower activity against B. subtilis with MIC₅₀ of 1.76 uM. The resistance frequency was calculated at around 4 x 10^"9.

[00284] Avasimibe mechanism of action

[00285] To determine if avasimibe targets folate biosynthesis in a manner similar to other sulfonamide drugs, the inhibition assay was repeated with inclusion of 50 μΜ tetrahydrofolate (THF) or 100 μΜ dihydrofolate (DHF). As shown in FIG. 3, the addition of THF or DHF did not rescue inhibition of growth of S. aureus by avasimibe, indicating that avasimibe does not target folate biosynthesis.

[00286] To determine if avasimibe functions as an ACAT inhibitor, the inhibition assay was repeated with inclusion of 50 μΜ cholesterol. As shown in FIG. 3, the addition of cholesterol did not rescue inhibition of growth of S. aureus by avasimibe, indicating that avasimibe does not affect S. aureus growth through ACAT inhibition.

Example 2: S. aureus killing with avasimibe over time

[00287] The antibacterial activity of avasimibe was evaluated by exposing S. aureus bacteria to avasimibe and evaluating change in CFU over time. Briefly, a Staphylococcus aureus bacterial suspension was prepared in MHB with the start inoculum of ~3xl0⁶ cell/mL, and cells were treated with 2 μΜ, 4 μΜ, 8 μΜ of avasimibe in a 37°C incubator with constant shaking at 200rpm. DMSO treated groups were served as control. 100 μΐ_^ of the treated bacterial suspension at different time intervals were streaked on Tryptic Soy Agar (TSA) plates and incubated at 37 °C overnight. Colony forming units (CFU) were counted and the time-killing curves were obtained by plotting the change of CFU from the inoculums. FIG. 4 shows the time-killing curve, which indicates that avasimibe is a potent bactericidal compound which kills bacteria rather than inhibit their growth, with a 10² fold reduction in the CFU number over a treatment period of 4 hours, and 10⁶ fold reduction within 8 hours.

Example 3: Avasimibe-drug interaction assay

[00288] Combination therapy remains a cornerstone especially important for drug resistant pathogen treatment, and any novel drug often must demonstrate compatibility with established antibiotics. Thus, activity of avasimibe against S. aureus in the presence of a panel of different classes of antibiotics (including kanamycin, erythromycin, trimethoprim, sulfamethoxazole and ciprofloxacin) was assessed via a

checkerboard assay. Briefly, overnight bacterial cultures were diluted 1 : 1000 with fresh MHB medium and further cultured in 37°C incubator for 4 hours to reach log growth phase. Bacterial cultures were then adjusted to approximately 2X10⁵ CFU/mL with fresh MHB medium as a bacterial suspension. A total of 25 μΐ_^ of MHB was distributed into each well of a clear-bottom 384-well plate (Greiner). Avasimibe was serially diluted by 2 fold along the ordinate, while the other antibiotic was diluted along the abscissa. Then 25 μΐ_^ of the Staphylococcus aureus bacterial suspension was added to each well. Each microtiter well was inoculated with a final volume of 50 μί bacterial inoculum of l xlO⁵ cell/mL, and the plates were incubated at 37 °C for 16 hours. All the experiments were tested in triplicate. To identify the drug interactions between avasimibe and other antibiotics, fractional inhibitory concentration index (∑FICI) was calculated with Formula A: ∑FICI = FIC [A] + FIC [B] (Formula A),

where FIC [A] is the MIC of drug avasimibe in the combination/MIC of drug avasimibe used alone, FIC [B] is the MIC of drug B (the other antibiotic) in the combination MIC of drug B alone. The interaction was defined as synergistic if the∑FICI was < 0.5, additive if the∑FICI was 0.5 to 1, indifferent if the∑FICI was 1 to 4, and antagonistic if the∑FICI was > 4.

[00289] Avasimibe demonstrated additive effects on inhibiting S. aureus growth in combination with erythromycin, trimethoprim, sulfamethoxazole and ciprofloxacin, as assessed by determining the average fractional inhibitory concentration index (∑FICI), with average∑FICI = 0.75, 1.0, 1.5 and 1.0, respectively. Moreover, aavasimibe exerts significant synergistic activity when tested in combination with the

aminoglycosides class antibiotic kanamycin, with∑FICI=0.28, as shown in FIG. 5. The darker squares shown in FIG. 5 (top left corner) indicate a smaller∑FICI value, while the lighter squares (bottom right corner) indicate a higher∑FICI value. The legend (scale from 0 to 100) shows the darkest squares have a lower∑FICI value and the lighter squares have a higher∑FICI value. These results suggest that avasimibe is a suitable drug candidate for treatment of Staphylococcal infection.

[00290] A panel of other aminoglycosides will be tested in combination with avasimibe, potentially including amikacin, tobramycin, dibekacin, gentamicin, sisomicin, netilmicin, neomycins, streptomycin, paromomycin, and verdamicin.

Example 4: In vivo efficacy evaluation with S. aureus systemic infection model of murine

[00291] MRSA strain Sanger 252 is grown to early-logarithmic phase in Todd-Hewitt broth, washed with phosphate-buffered saline, and ~ 5X10⁹ colony-forming units are injected intraperitoneally (i.p.) into 8 week old female CD 1 mice. One hour after infection, the mice are divided into four groups and treated i.p. with avasimibe (either 50 or 10 mg/kg), positive control vancomycin ( 15 mg/kg) or vehicle control (n = 8 per group). Treatment is continued IP once daily throughout the study, and mortality is monitored for 7 days. Moribund mice are humanely euthanized.

Example 5: Treatment of S. aureus with avasimibe and anti-S. aureus antibody

[00292] MRSA strain Sanger 252 is grown to early-logarithmic phase in Todd-Hewitt broth, washed with phosphate-buffered saline, and ~ 5X10⁹ colony-forming units are injected intraperitoneally (i.p.) into 8 week old female CD1 mice. One hour after infection, the mice are divided into four groups and treated i.p. with avasimibe (either 50 or 10 mg/kg) and anti-iS^*. aureus antibody, positive control vancomycin ( 15 mg/kg) or vehicle control (n = 8 per group). Treatment is continued IP once daily throughout the study, and mortality is monitored for 7 days. Moribund mice are humanely euthanized.

Example 6: Treatment of S. aureus with avasimibe and anti-S. aureus antibody

[00293] MRSA strain Sanger 252 is grown to early-logarithmic phase in Todd-Hewitt broth, washed with phosphate-buffered saline, and ~ 5X10⁹ colony-forming units are injected intraperitoneally (i.p.) into 8 week old female CD1 mice who are currently undergoing treatment with an anti-iS^*. aureus antibody. One hour after infection, the mice are divided into four groups and treated i.p. with avasimibe (either 50 or 10 mg/kg), positive control vancomycin (15 mg/kg) or vehicle control (n = 8 per group). Treatment is continued IP once daily throughout the study and mortality is monitored for 7 days. Moribund mice are humanely euthanized. Example 7: Treatment of S. aureus with avasimibe and tefibazumab

[00294] MRSA strain Sanger 252 is grown to early-logarithmic phase in Todd-Hewitt broth, washed with phosphate-buffered saline, and ~ 5X10⁹ colony-forming units are injected intraperitoneally (i.p.) into 8 week old female CDl mice. One hour after infection, the mice are divided into four groups and treated i.p. with avasimibe (either 50 or 10 mg/kg) and tefibazumab, positive control vancomycin ( 15 mg/kg) or vehicle control (n = 8 per group). Treatment is continued IP once daily throughout the study, and mortality is monitored for 7 days. Moribund mice are humanely euthanized.

Example 8: Treatment of S. aureus with avasimibe and tefibazumab

[00295] MRSA strain Sanger 252 is grown to early-logarithmic phase in Todd-Hewitt broth, washed with phosphate-buffered saline, and ~ 5X10⁹ colony-forming units are injected intraperitoneally (i.p.) into 8 week old female CDl mice who are currently undergoing treatment with tefibazumab. One hour after infection, the mice are divided into four groups and treated i.p. with avasimibe (either 50 or 10 mg/kg), positive control vancomycin (15 mg/kg) or vehicle control (n = 8 per group). Treatment is continued IP once daily throughout the study, and mortality is monitored for 7 days. Moribund mice are humanely euthanized.

[00296] The preceding merely illustrates the principles of this disclosure. It will be appreciated that those skilled in the art will be able to devise various arrangements which, although not explicitly described or shown herein, embody the principles of the invention and are included within its spirit and scope.

Furthermore, all examples and conditional language recited herein are principally intended to aid the reader in understanding the principles of this disclosure and the concepts contributed by the inventors to furthering the art, and are to be construed as being without limitation to such specifically recited examples and conditions. Moreover, all statements herein reciting principles, aspects, and embodiments of the invention as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Additionally, it is intended that such equivalents include both currently known equivalents and equivalents developed in the future, i.e., any elements developed that perform the same function, regardless of structure. The scope of the present disclosure, therefore, is not intended to be limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of the present disclosure is embodied by the appended claims.

[00297] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the disclosure. It should be understood that various alternatives to the embodiments of the disclosure described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the disclosure and that methods and structures within the scope of these claims and their equivalents be covered thereby. [00298] All references cited herein are incorporated by reference in their entirety and for all purposes to the same extent as if each individual publication or patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.

Claims

What is claimed is:

1. A method of treating a bacterial infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of an antibacterial compound of Formula (I)

Formula (I)

or pharmaceutically acceptable salt or solvate thereof, wherein:

2. The method of claim 1, wherein the antibacterial compound of Formula (I) has the structure of

Formula (la)

Formula (la)

or pharmaceutically acceptable salt or solvate thereof, wherein:

X¹, X², X³, X⁴, and X⁵ are independently selected from N, CH, and CR⁴;

Y¹, Y², Y³, Y⁴, and Y⁵ are independently selected from N, CH, and CR⁴;

p is 0, 1, 2, 3, 4 or 5.

The method of claim 2, wherein the antibacterial compound of Formula (la) has the structure of Formula (lb)

Formula (lb)

or pharmaceutically acceptable salt or solvate thereof, wherein:

optionally be substituted with -F, -OH, and -OMe, and C₃-C₇cycloalkyl;

The method of claim 3, wherein the antibacterial compound of Formula (lb) has the structure of avasimibe

or pharmaceutically acceptable salt or solvate thereof.

The method of any of claims 1 -4, wherein a causative agent of the bacterial infection is a Gram- positive bacteria, and the subject is infected with the causative agent. The method of claim 5, wherein the Gram-positive bacteria comprises Staphylococcus, Bacillus, Enterococcus , Streptococcus, Clostridium, or a combination thereof.

The method of any of claims 1-6, wherein a causative agent of the bacterial infection is a drug- resistant bacteria, and the subject is infected with the causative agent.

The method of claim 7, wherein the drug is an antibiotic.

The method of claim 8, wherein the antibiotic comprises a polymyxin antibiotic, a beta-lactam antibiotic, a fluoroquinolone antibiotic, a cephalosporin antibiotic, a carbapenem antibiotic, a cephalosporin antibiotic, or a combination thereof.

10. The method of any of claims 5-9, wherein treating the bacterial infection comprises reducing the population of viable causative agent in the subject as compared to the population of viable causative agent in the subject prior to administration of the antibacterial compound of Formula (I).

11. The method of any of claims 5-9, wherein treating the bacterial infection comprises reducing growth, replication and/or propagation of the causative agent in the subject by at least about 20%, 40%, 60%,

80% or 90% after administration of the antibacterial compound of Formula (I).

12. The method of any of claims 1-11, wherein the subject is administered an additional antibacterial compound.

13. The method of any of claims 1-12, wherein the subject is administered an antibody or an antigen- binding fragment of the antibody.

14. A method of exerting an antibacterial effect on a bacteria, the method comprising contacting the bacteria with a compound of Formula (I)

Formula (I)

or pharmaceutically acceptable salt or solvate thereof, wherein:

R¹ and R³ are independently selected from substituted or unsubstituted Ci-Ci₀alkyl, substituted or unsubstituted C₃-Ci₀cycloalkyl, substituted or unsubstituted C₂-Ci₀heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, wherein if R¹ and R³ are substituted then R¹ and R³ are independently substituted with one or more R⁴ groups; each R⁴ is independently selected from D, -OR⁵, -SR⁵, -F, -CI, -Br, -I, -C(0)R⁵, -C0₂R⁵, -CN, - N0₂, -N(R⁶)(R⁷), substituted or unsubstituted Ci-C₇alkyl, substituted or unsubstituted C₃- C₇cycloalkyl, substituted or unsubstituted C₂-C₆heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; each R⁵ is independently selected from H, substituted or unsubstituted Ci-C₆alkyl, substituted or unsubstituted C₃-C₇cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

The method of claim 14, wherein the antibacterial compound of Formula (I) has the structure of avasimibe

or pharmaceutically acceptable salt or solvate thereof.

The method of claim 14 or claim 15, wherein contacting comprises bringing the bacteria in proximity to the compound of Formula (I) such that the compound of Formula (I) exerts the antibacterial effect on the bacteria.

The method of any of claims 14-16, wherein the antibacterial effect comprises: (i) killing the bacteria, (ii) reducing growth of the bacteria, (iii) reducing replication of the bacteria, (iv) reducing propagation of the bacteria, (v) reducing viable bacteria population, or (vi) a combination of any of (i)-(v).

The method of any of claims 14-17, wherein the antibacterial effect is evaluated by measuring the minimal inhibitory concentration 50% (MIC50) of the compound of Formula (I) for the bacteria, and the MIC50 is less than about 50 μΜ, 40 μΜ, 30 μΜ, 20 μΜ, 10 μΜ, 1 μΜ, 100 ηΜ, 10 ηΜ, 1 ηΜ, 100 ρΜ or 10 ρΜ.

19. The method of any of claims 14-18, wherein contacting comprises administering the compound of Formula (I) to a subject infected with the bacteria.

20. The method of any of claims 14-18, wherein contacting comprises combining the compound of

Formula (I) with the bacteria in an in vitro solution.

21. The method of any of claims 14-18, wherein contacting comprises providing the compound of

Formula (I) on a surface comprising or suspected of comprising the bacteria.

22. The method of any of claims 14-21, wherein the bacteria has resistance to a drug.

23. A method of identifying antibacterial activity of a compound of Formula (I) for a test bacteria, the method comprising contacting the test bacteria with a compound of Formula (I)

Formula (I)

or pharmaceutically acceptable salt or solvate thereof, wherein:

independently selected from H, -F, -CI, -Br, -I, -OR⁵, -C(0)R⁵, substituted or unsubstituted Ci-

- I l l - C₇alkyl; substituted or unsubstituted C₃-C₇cycloalkyl, substituted or unsubstituted C₂- C₇heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; n is 1, 2, 3, or 4.

24. The method of claim 23, wherein if the compound of Formula (I) kills and/or inhibits the test bacteria after contact, the compound of Formula (I) is identified as having antibacterial activity for the test bacteria.

25. The method of claim 24, wherein inhibition of the test bacteria comprises (i) reducing growth of the bacteria, (ii) reducing replication of the bacteria, (iii) reducing propagation of the bacteria, (iv) reducing viable bacteria population, or (v) a combination of any of (i)-(iv).

26. The method of claim 24 or claim 25, wherein contacting comprises combining the compound of Formula (I) with the test bacteria in an in vitro solution.

27. The method of claim 24 or claim 25, wherein contacting comprises providing the compound of

Formula (I) on a surface comprising the test bacteria.

28. The method of claim 24 or claim 25, wherein contacting comprises administering the compound of Formula (I) to a subject infected with the test bacteria.

29. A combination comprising first agent having Formula (I)

Formula (I)

The combination of claim 29, wherein the second agent comprises (i) an antibacterial compound and/or (ii) an antibody or an antigen-binding fragment of the antibody.