WO2024158908A1 - Methods of treating bacterial infections - Google Patents

Abstract

This disclosure relates to methods of treating a bacterial infection comprising administering an effective amount of a compound or compounds identified herein to a subject in need thereof. In certain embodiments, the compound is salmeterol, lomerizine, and/or fendiline. In certain embodiments, the bacterial infection is a multidrug resistant bacterial infection. In certain embodiments, the subject is infected with or diagnosed with an Acinetobacter baumannii infection. In certain embodiments, compounds disclosed herein are administered in combination with a cationic antibiotic or a polymyxin such a colistin.

Description

METHODS OF TREATING BACTERIAL INFECTIONS

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No. 63/440,784 filed January 24, 2023. The entirety of this application is hereby incorporated by reference for all purposes.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with government support under AI072219 awarded by the National Institutes of Health. The government has certain rights in the invention.

BACKGROUND

Antibiotic resistance in bacteria is a global health emergency. The “poster child” for antibiotic resistance in Gram-negative bacteria is Acinetobacter baumannii, a highly problematic opportunistic pathogen. A. baumannii infections represents the leading cause of secondary bacterial pneumonia in patients infected with viruses such as SARS-CoV-2. The development of antibiotic resistance in A. baumannii has reached a crisis stage. Thus, there is a need to identify improved treatments.

Peyclit et al. report in vitro screening of a drug library against multidrug-resistant and extensively drug-resistant bacteria. Antibiotics, 2022, 11, 291.

Czyz et al. report host-directed antimicrobial drugs with broad-spectrum efficacy against intracellular bacterial pathogens. mBio, 2014, 5(4):e01534-14.

Singh et al. report quorum sensing inhibitors. Iranian Journal of Pharmaceutical Research, (2021), 20 (2): 486-514.

References cited herein are not an admission of prior art.

SUMMARY

This disclosure relates to methods of treating a bacterial infection comprising administering an effective amount of a compound or compounds identified herein to a subject in need thereof. In certain embodiments, the compound is salmeterol, lomerizine, fendiline, or combinations thereof. In certain embodiments, the bacterial infection is a multidrug resistant gram-negative bacterial infection.

In certain embodiments, the subject is diagnosed with a multi drug resistant bacterial infection. In certain embodiments, the subject is infected with or diagnosed with w.Acinetobacter baumannii infection. In certain embodiments, a compound or compounds disclosed herein are administered in combination with another antibiotic such as a cationic antibiotic or a polymyxin such a colistin.

In certain embodiments, this disclosure contemplates the production of a medicament comprising a compound or compounds disclosed herein, such as salmeterol, lomerizine, fendiline, or combinations thereof, and optionally another antibacterial agent, useful for treating bacterial or other microbial infections disclosed herein. In certain embodiments, this disclosure contemplates kits and pharmaceutical compositions comprising compounds disclosed herein and a pharmaceutically acceptable excipient and optionally another antibacterial agent.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

Figure 1 shows data indicating bactericidal activity of lomerizine against A. baumannii 17978 AadeB Aadel surA::T26. After 24 hours incubation, MIC wells were diluted and plated to enumerate colony forming units (CFU)/ml +/- S.D. for three replicates.

Figure 2 shows data on inhibitory activity of lomerizine and fendiline against exponential A. baumannii 17978 AadeB AadeJ surA::T26. A. baumannii 17978 AadeB AadeJ surA::T26 cells were grown to early exponential phase then treated with 4X MIC lomerizine (64 ug/ml), 4X MIC fendiline (32 ug/ml), or DMSO (control). Optical density at 600 nm (OD600) was monitored each hour shaking cultures at 37°C.

DETAILED DESCRIPTION

Before the present disclosure is described in greater detail, it is to be understood that this disclosure is not limited to embodiments described, and as such may, of course, vary. It is also to be understood that the term "embodiment" used herein is an example, and the claims are not necessarily limited to such example, since the scope of the present disclosure will be limited only by the appended or ultimately amended claims. The original presented claims are just a starting point, and the applicants preserve the righto present new claims and amendments in the future provided the new or amended claims are supported in the specification and or drawings.

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 disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described.

All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present disclosure is not entitled to antedate such publication by virtue of prior disclosure. Further, the dates of publication provided could be different from the actual publication dates that may need to be independently confirmed.

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 disclosure. Any recited method can be carried out in the order of events recited or in any other order that is logically possible.

Embodiments of the present disclosure will employ, unless otherwise indicated, techniques of medicine, organic chemistry, biochemistry, molecular biology, pharmacology, and the like, which are within the skill of the art. Such techniques are explained fully in the literature.

It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. For example, “an antibiotic” refers to one or a combination of antibiotics. In this specification and in the claims that follow, reference will be made to several terms that shall be defined to have the following meanings unless a contrary intention is apparent.

As used in this disclosure and claim(s), the words "comprising" (and any form of comprising, such as "comprise" and "comprises"), "having" (and any form of having, such as "have" and "has"), "including" (and any form of including, such as "includes" and "include") or "containing" (and any form of containing, such as "contains" and "contain") have the meaning ascribed to them in U.S. Patent law in that they are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. "Consisting of or "consists essentially of or the like, when applied to methods and compositions encompassed by the present disclosure refers to compositions like those disclosed herein that exclude certain prior art elements to provide an inventive feature of a claim, but which may contain additional composition components or method steps, etc., that do not materially affect the basic and novel characteristic(s) of the compositions or methods, compared to those of the corresponding compositions or methods disclosed herein.

As used herein, "subject" refers to any animal, preferably a human patient, livestock, or domestic pet.

As used herein, the terms "treat" and "treating" are not limited to the case where the subject (e.g., patient) is cured and the disease is eradicated. Rather, embodiments, of the present disclosure also contemplate treatment that merely reduces symptoms, and/or delays disease progression.

As used herein, the term "combination with" when used to describe administration with an additional treatment means that the agent may be administered prior to, together with, or after the additional treatment, or a combination thereof.

The term "effective amount" refers to that amount of a compound or pharmaceutical composition described herein that is sufficient to effect the intended application including, but not limited to, disease treatment, as illustrated below. The therapeutically effective amount can vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The specific dose will vary depending on, for example, the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other agents, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

A bacterial isolate from a clinical sample can be tested for antibiotic resistance in vitro prior to administering an antibiotic to a patient, using conventional susceptibility tests, such as Etests and broth microdilution. Antibacterial susceptibility tests are typically performed in suspension assays (e.g., broth microdilution assay) or in agar plate assays (e.g., disk diffusion assay). An Epsilometer test (Etest) is a strip containing an antibiotic gradient used to determine whether or not a specific bacterial strain is susceptible to the action of a specific antibiotic. When the Etest strip is placed on an agar surface, the antibiotic gradient on the strip is transferred to the agar creating an imprint of the gradient on the strip in the agar. The bacterial growth becomes visible after incubation and an inhibition ellipse centered along the strip can be seen. The MIC (Minimum Inhibitory Concentration) value is read from the scale where the ellipse edge intersects the strip.

In certain embodiments, this disclosure relates to methods of treating a bacterial infection or other microbial infection comprising administering an effective amount of a compound or compounds identified herein to a subject in need thereof. In certain embodiments, the compound is salmeterol, lomerizine, and/or fendiline. In certain embodiments, the bacterial infection is a multidrug resistant gram-negative bacterial infection, the subject is infected with or diagnosed with Acinetobacter baumcmnii. In certain compounds disclosed herein are administered in combination with a cationic antibiotic or a polymyxin such a colistin.

The term “cationic antibiotic” refers to any variety of antibiotics that contain a protonated amine at physiological pH, e.g., contains one or more quaternary ammonium ions, amine, or guanidine groups. Many naturally occurring antimicrobial peptides and aminoglycoside are cationic antibiotics. Antimicrobial peptides typically comprise lysine and arginine amino acids which provide cations at physiological pH. Antimicrobial peptides may have a variety of amino acid sequences; however, they typically fold or present a positively charged domain or face and hydrophobic domain or face which facilitates binding to a lipid bilayer. Aminoglycosides are saccharide or polysaccharide complexes that contain cationic groups, e.g., amino groups or guanidine groups or combinations.

As used herein, the term “polymyxin” refers to cyclic peptides having multiple diaminobutyric acids and N-terminal lipid substituents. Polymyxins typically contain lipophilic amino acids, e.g., Leu, He, Vai, or Nva (Norvaline) within the peptide ring which may be D- or L- amino acids.

As used herein, the term “colistin” refers to a polymyxin and salts thereof containing a D- Leu and L-Leu amino acids withing the peptide ring and a 5-methyl hexyl or 5 -methylheptyl N- terminal lipids (preparations of colistin may contain different amounts of these lipid components). Also contemplated are derivatives wherein the gama-diaminobutyric acids are optionally nitrogen substituted prodrugs with methanesulfonate, such as in the case of pentasodium colistin methanesulfonate. See Suzuki et al. Studies on the chemical structure of colistin. I. Fractionation, molecular weight determination, amino acid and fatty acid composition. J. Biochem. 54(1), 25-33 (1963).

The term "prodrug" refers to an agent that is converted into a biologically active form in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. They may, for instance, be bioavailable by oral administration whereas the parent compound is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. A prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis. Typical prodrugs are pharmaceutically acceptable esters. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of an alcohol or acetamide, formamide, methanesulfonate, and benzamide derivatives of an amine functional group in the active compound and the like.

In certain embodiments, this disclosure contemplates methods and compositions disclosed herein for use in treating a variety of microbial infections using compounds disclosed herein. In certain embodiments, the microbes are antimicrobial-resistant gram positive or gram negative bacterial strains selected from, but not limited to, Acinetobacter baumcmnii, Abiotrophia defectiva, Acholeplasma spp., Actinobaculum suis, Actinomyces bovis, Actinomyces europaeus, Actinomyces georgiae, Actinomyces gerencseriae, Actinomyces graevenitzii, Actinomyces hordeovulneris, Actinomyces israelii serotype II, Actinomyces israelii, Actinomyces meyeri, Actinomyces naeshmdii, Actinomyces neuii, Actinomyces odontolyticus, Actinomyces radingae, Actinomyces spp, Actinomyces turicensis, Actinomyces viscosus, Alloscardovia omnicolens, Anaerococcus hydrogenalis, Anaerococcus lactolyticus, Anaerococcus murdochii, Anaerococcus octavius, Anaerococcus prevotii, Anaerococcus tetradius, Anaerococcus vaginalis, Arcanobacterium (Actinomyces) bernardiae, Arcanobacterium (Actinomyces) pyogenes, Arcanobacterium bernardiae, Arcanobacterium cardiffensis, Arcanobacterium funkei, Arcanobacterium haemolyticum, Arcanobacterium houstonensis, Arcanobacterium linguae, Arcanobacterium pyogenes (Actinomyces pyogenes), Arthrobacter, Atopobium minutum, Atopobium parvulum, Atopobium rimae, Atopobium spp, Atopobium vaginae, Bacillus anthracis, Bacillus cereus, Bacillus circulans, Bacillus licheniformis, Bacillus megaterium, Bacillus melaninogenicus, Bacillus pumilus, Bacillus sphaericus, Bacillus subtilis, beta haemolytic Steptococcus spp, Bifidobacteria adolescentis, Bifidobacteria dentium, Bifidobacteria scardovii, Bifidobacteria, Brevibacillus brevis, Brevibacillus laterosporus, Brevibacterium, Bulleidia extructa, Catabacter hongkongensis, CDC coryneform groups F-l and G, Clostridiium tetani, Clostridium baratii, Clostridium bifermentans, Clostridium botulinum (types A, B, C, D, E, F, G), Clostridium botulinum, Clostridium butyricum, Clostridium chauvoei, Clostridium colinum, Clostridium difficile, Clostridium haemolyticum, Clostridium histolyticum, Clostridium novyi type A, Clostridium novyi type B, Clostridium novyi, Clostridium perfringens type A, Clostridium perfringens types A-E, Clostridium perfringens, Clostridium piliforme, Clostridium ramosum, Clostridium septicum, Clostridium sordelli, Clostridium sphenoides, Clostridium spiroforme, Clostridium spp, Clostridium tertium, Clostridium tetani, Collinsella aerofaciens, Corynebacterium accolens, Corynebacterium afermentans afermentans, Corynebacterium afermentans lipophilum, Corynebacterium amycolatum, Corynebacterium argentoratense, Corynebacterium aurimucosum, Corynebacterium auris, Corynebacterium bovis, Corynebacterium confusum, Corynebacterium cystidis, Corynebacterium diphtheria, Corynebacterium freneyi, Corynebacterium glucuronolyticum, Corynebacterium jeikeium, Corynebacterium kroppenstedtii, Corynebacterium kutscheri, Corynebacterium lipophiloflavum, Corynebacterium macginleyi, Corynebacterium matruchotii, Corynebacterium minutissimum, Corynebacterium pilosum, Corynebacterium propinquum, Corynebacterium pseudodiphtheriticum, Corynebacterium pseudotuberculosis, Corynebacterium renale, Corynebacterium riegelii, Corynebacterium simulans, Corynebacterium striatum, Corynebacterium sundvallense, Corynebacterium thomssensii, Corynebacterium tuber culostearum, Corynebacterium ulcerans, Corynebacterium urealyticum, Corynebacterium xerosis, Crossiella equi, Dermabacter, Dermatophilus congolense, Dermatophilus congolensis, Eggerthella brachy, Eggerthella hongkongensis, Eggerthella infirmum, Eggerthella lenta, Eggerthella minutum, Eggerthella nodatum, Eggerthella saphenum, Eggerthella sinensis, Eggerthella sulci, Eggerthella tenue, Eggerthella, Enterococcus avium, Enterococcus bovis, Enterococcus casseliflavus/fiavescens, Enterococcus cecorum, Enterococcus dispar, Enterococcus durans, Enterococcus faecalis, Enterococcus faecium, Enterococcus gallinarum, Enterococcus gilvus, Enterococcus hirae, Enterococcus italicus, Enterococcus malodoratus, Enterococcus mundtii, Enterococcus pallens, Enterococcus pseudoavium, Enterococcus raffinosus, Enterococcus sanguinicola, Enterococcus spp, Erysipelothrix rhusiopathiae, Eubacterium, Filifactor alocis, Finegoldia magna, Gallicola barnesae, Gemella asaccharolytica, Gemella bergeri, Gemella cuniculi, Gemella haemolysans, Gemella morbillorum, Gemella palaticanis, Gemella sanguinis, Gordonia spp., Granulicatella adiacens, Granulicatella elegans, Granulicatella para-adiacens, Kytococcus schroeteri, Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus fermentum, Lactobacillus gasseri, Lactobacillus iners, Lactobacillus plantarum, Lactobacillus rhamnosus, Lactobacillus species, Lactobacillus ultunensis, Leifsonia aquatic, Leuconostoc citreum, Leuconostoc lactis, Leuconostoc mesenteroides, Leuconostoc paramesenteroides, Leuconostoc pseudomesenteroides, Listeria grayi, Listeria innocua, Listeria ivanovii, Listeria monocytogenes, Listeria seeligeri, Listeria welshimeri, Microbacterium, Mobiluncus curtisii, Mobiluncus mulieris, Mobiluncus spp, Mogibacterium timidum, Mogibacterium vescum, Moryella indoligenes, Mycobacterium senegalense, Mycobacterium abscessus, Mycobacterium africanum, Mycobacterium arupense, Mycobacterium asiaticum, Mycobacterium aubagnense, Mycobacterium avium complex, Mycobacterium avium subsp paratuberculosis, Mycobacterium avium, Mycobacterium bolletii, Mycobacterium bovis, Mycobacterium branded, Mycobacterium canettii, Mycobacterium caprae, Mycobacterium celatum, Mycobacterium chelonae, Mycobacterium chimaera, Mycobacterium colombiense, Mycobacterium conceptionense, Mycobacterium conspicuum, Mycobacterium elephantis, Mycobacterium farcinogenes, Mycobacterium florentinum, Mycobacterium fortuitum group, Mycobacterium genavense, Mycobacterium goodii, Mycobacterium haemophilum, Mycobacterium heckeshornense, Mycobacterium heidelbergense, Mycobacterium houstonense, Mycobacterium immunogenum, Mycobacterium interjectum, Mycobacterium intr acellular e, Mycobacterium kansasii, Mycobacterium lacus, Mycobacterium lentiflavum, Mycobacterium leprae, Mycobacterium lepraemurium, Mycobacterium mageritense, Mycobacterium malmoense, Mycobacterium marinum, Mycobacterium massiliense, Mycobacterium microti, Mycobacterium montefiorense (eels), Mycobacterium moracense, Mycobacterium mucogenicum, Mycobacterium nebraskense, Mycobacterium neoaurum, Mycobacterium novocastrense, Mycobacterium palustre, Mycobacterium paratuberculosis (Johne's Disease), Mycobacterium parmense, Mycobacterium phlei, Mycobacterium phocaicum, Mycobacterium pinnipedii, Mycobacterium porcinum, Mycobacterium pseudoshottsii (fish), Mycobacterium pseudotuberculosis, Mycobacterium saskatchewanense, Mycobacterium scrofulaceum, Mycobacterium senuense, Mycobacterium septicum, Mycobacterium simiae, Mycobacterium smegmatis, Mycobacterium spp, Mycobacterium szulgai, Mycobacterium terrae/chromogenicum complex, Mycobacterium triplex, Mycobacterium tuberculosis, Mycobacterium tusciae, Mycobacterium ulcerans, Mycobacterium wolinskyi, Mycobacterium xenopi, Mycobacterium, Nocardia asteroides, Nocardia brasiliensis, Nocardia fiarcinica, Nocardia nova, Nocardia otitidiscaviarum, Nocardia spp, Nocardia transvalensis, Oerskovia, Olsenella oral spp, Olsenellaprofiuse, Olsenellauli, Oribacterium sinus, Paenibacillus alvei, Parvimonas micra, Pediococcus, Peptococcus indolicus, Peptococcus niger, Peptoniphilus asaccharolyticus, Peptoniphilus gorbachii, Peptoniphilus harei, Peptoniphilus indolicus, Peptoniphilus ivorii, Peptoniphilus lacrimalis, Peptoniphilus olsenii, Peptostreptococcus anaerobius, Peptostreptococcus stomatis, Propionibacterium acnes, Propionibacterium granulosum, Propionibacterium propionicum, Propionibacterium, Pseudoramibacter alactolyticus, Rhodococcus equi, Rhodococcus erythropolis, Rhodococcus fasciens, Rhodococcus rhodochrous, Rothia, Ruminococcus productus, Slackia exigua, Slackia heliotrinireducens, Solobacterium moorei, Staphylococcus arlettae, Staphylococcus aureus subsp. anaerobius, Staphylococcus aureus, Staphylococcus auricularis, Staphylococcus capitis subsp. capitis, Staphylococcus capitis subsp. urealyticus, Staphylococcus capitis, Staphylococcus caprae, Staphylococcus carnosus, Staphylococcus caseolyticus, Staphylococcus chromogenes, Staphylococcus cohnii subsp. cohnii, Staphylococcus cohnii subsp. urealyticus, Staphylococcus cohnii, Staphylococcus condimenti, Staphylococcus delphini, Staphylococcus epidermidis, Staphylococcus equorum, Staphylococcus felis, Staphylococcus fleurettii, Staphylococcus gallinarum, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus hyicus, Staphylococcus intermedius, Staphylococcus kloosii, Staphylococcus lentus, Staphylococcus lugdunensis, Staphylococcus lutrae, Staphylococcus muscae, Staphylococcus nepalensis, Staphylococcus pasteuri, Staphylococcus pettenkoferi, Staphylococcus piscifermentans, Staphylococcus pseudintermedius, Staphylococcus pulvereri, Staphylococcus saccharolyticus, Staphylococcus saprophyticus, Staphylococcus schleiferi subsp. coagulans, Staphylococcus schleifieri, Staphylococcus sciuri, Staphylococcus simiae, Staphylococcus simulans, Staphylococcus spp, Staphylococcus succinus, Staphylococcus vitulinus, Staphylococcus warneri, Staphylococcus xylosus, Staphylococcus vitulinus, Stomatococcus mucilaginosus (reclassified as Rothia mucilaginosa), Streptococcus agalactiae, Streptococcus anginosus species group (Streptococcus interne dius, Streptococcus constellatus, and Streptococcus anginosus), Streptococcus bovis species group (S. gallolyticus subsp. gallolyticus (formerly S. bovis biotype I), Streptococcus bovis, Streptococcus canis, Streptococcus dysgalactiae subsp. dysgalactiae, S. equi subsp. equi, S. equi subsp. zooepidemicus, S. porcinus, S. canis, S. suis, S. iniae), Streptococcus dysgalactiae subsp. equisimilis, Streptococcus dysgalactiae, Streptococcus equi (Streptococcus equi subsp equi), Streptococcus equi subsp. zooepidemicus, Streptococcus equi, Streptococcus equinus, Streptococcus equisimilis (Streptococcus dysgalactiae subsp equisimilis), Streptococcus gallolyticus subsp. pasteurianus (formerly S. bovis biotype II/2), Streptococcus infantarius subsp Infantarius, Streptococcus lutetiensis (formerly S. bovis biotype II/ 1), Streptococcus mitis species group (S. cristatus, S. infantis, S. mitis, S. oxalis, S. peroris, S. orisratti), and Streptococcus mutans species group (S. cricetus, S. downei, S. ferus, S. hyovaginalis, S. macaccae, S. mutans, S. ratti, S. sobrinus, Sanguinis Group, S. gordonii, S. parasanguinis, S. sanguinis), Streptococcus pneumoniae, Streptococcus porcinus, Streptococcus pyogenes, Streptococcus salivarius species group (S. alactolyticus, S. hyointestinalis, S. infantarius, S. salivarius, S. thermophilus, S. vestibularis), Streptococcus spp, Streptococcus suis, Streptococcus uberis, Streptococcus zooepidemicus (Streptococcus equi subsp zooepidemicus), Streptococcus zooepidemicus, Trueperella abortisuis, Trueperella bernardiae, Trueperella bialowiezensis, Trueperella bonasi, Trueperella pyogenes (Arcanobacterium pyogenes), Tsukamurella spp., Turicella, and Turicibacter sanguine, Acetic acid bacteria, Acinetobacter spp., Acinetobacter baumannii, Agrobacterium tumefaciens, Anaerobiospirillum, Anaerolinea thermolimosa, Anaerolinea thermophila, Arcobacter, Arcobacter skirrowii, Armatimonas rosea, Azotobacter salinestris, Bacteroides, Bacteroides jragilis, Bacteroides ureolyticus, Bacteroidetes, Bartonella, Bartonella japonica, Bartonella henselae, Bartonella koehlerae, Bartonella taylorii, Bdellovibrio, Brachyspira, Bradyrhizobium japonicum, Brucella, Brucella abortus, Brucella canis, Brucella ceti, Brucella inopinata, Brucella melitensis, Brucella microti, Brucella neotomae, Brucella ovis, Brucella pinnipedialis, Brucella suis, Burkholderia, Burkholderia cenocepacia, Burkholderia cepacia, Burkholderia pickettii, Burkholderia thailandensis, Burkholderia ubonensis, Burkholderia udeis, Caldilinea aerophila, Campylobacter, Campylobacter coli, Campylobacter concisus, Campylobacter fetus, Campylobacter hyointestinalis, Campylobacter jejuni, Campylobacter lanienae, Campylobacter lari, Campylobacter mucosalis, Campylobacter pylori, Campylobacter rectus, Campylobacter showae, Campylobacter upsaliensis, Cardiobacterium hominis, Chlamydia, Chlamydia muridarum, Chlamydia pecorum, Chlamydia pneumoniae, Chlamydia psittaci, Chlamydia suis, Chlamydia trachomatis, Christensenella, Chthonomonas calidirosea, Citrobacter frendii, Citrobacter gillenii, Citrobacter Koseri, Citrobacter rodentium, Citrobacter werkmanii, Coxiella burnetii, Cyanobacteria, Cytophaga, Dehalogenimonas lykanthroporepellens, D esulfur obacter im atlanticum, Devosia pacifica, Devosia psychrophila, Devosia soli, Devosia subaequoris, Devosia submarina, Devosia yakushimensis, Dialister, Dictyoglomus thermophilum, Enterobacter, Enterobacter aerogenes, Enterobacter agglomerans, Enterobacter arachidis, Enterobacter asburiae, Enterobacter cancer ogenous, Enterobacter cloacae, Enterobacter cloacae complex, Enterobacter cawanii, Enterobacter dissolvens, Enterobacter gergoviae, Enterobacter helveticus, Enterobacter intermedius, Enterobacter kobei, Enterobacter ludqigii, Enterobacter pulveris, Enterobacter pyrinus, Enterobacter taylorae, Enterobacter turicensis, Enterobacter sakazakii, Enter obacteriaceae, Enterobacteriales, Escherichia, Escherichia albertii, Escherichia coli, Escherichia fergusonii, Escherichia hermannii, Escherichia vulneris, Fimbriimonas ginsengisoli, Flavobacterium, Francisella tularensis, Francisella novicida, Francisella guangzhouensis, Francisella halioticida, Francisella hispaniensis, Francisella holarctica, Francisella mediasiatica, Francisella noatunensis, Francisella noatunensis subsp. noatunensis, Francisella noatunensis subsp. orientalis, Francisella persica, Francisella philomiragia, Francisella philomiragia subsp. noatunensis, Francisella philomiragia subsp. philomiragia, Francisella piscicida, Francisella spp.,, Fusobacterium necrophorum, Fusobacterium nucleatum, Fusobacterium polymorphum, Haemophilus felis, Haemophilus haemolyticus, Haemophilus influenzae, Haemophilus pittmaniae, Helicobacter, Helicobacter acinonychis, Helicobacter anseris, Helicobacter bilis, Helicobacter canadensis, Helicobacter canis, Helicobacter hepaticus, Helicobacter muridarum, Helicobacter pametensis, Helicobacter pullorum, Helicobacter pylori, Helicobacter rodentium, Helicobacter salomonis, Kingella kingae, Klebsiella, Klebsiella granulomatis, Klebsiella michiganensis, Klebsiella oxytoca, Klebsiella pneumoniae, Klebsiella quasipneumoniae, Klebsiella terrigena, Klebsiella variicola, Kluyvera ascorbata, Kluyvera cryocrescens, Kozakia baliensis, Legionella, Legionella adelaidensis, Legionella anisa, Legionella beliardensis, Legionella birminghamensis, Legionella bozemanae, Legionella brunensis, Legionella busanensis, Legionella cardiaca, Legionella cherrii, Legionella cincinnatiensis, Legionella clemsonensis, Legionella donaldsonii, Legionella drancourtii, Legionella dresdenensis, Legionella drozanskii, Legionella dumoffii, Legionella erythra, Legionella fairfieldensis, Legionella fallonii, Legionella feeleii, Legionella geestiana, Legionella gormanii, Legionella gratiana, Legionella gresilensis, Legionella hackeliae, Legionella impletisoli, Legionella israelensis, Legionella jamestowniensis, Legionella jeonii, Legionella jordanis, Legionella lansingensis, Legionella londiniensis, Legionella longbeachae, Legionella lytica, Legionella maceachernii, Legionella massiliensis, Legionella micdadei, Legionella monrovica, Legionella moravica, Legionella nagasakiensis, Legionella nautarum, Legionella norrlandica, Legionella oakridgensis, Legionella parisiensis, Legionella pittsburghensis, Legionella pneumophila, Legionella quateirensis, Legionella quinlivanii, Legionella rowbothamii, Legionella rubrilucens, Legionella sainthelensi, Legionella santicrucis, Legionella shakespearei, Legionella spiritensis, Legionella steelei, Legionella steigerwaltii, Legionella taurinensis, Legionella tucsonensis, Legionella tunisiensis, Legionella wadsworthii, Legionella waltersii, Legionella w or sleiensis, Legionella yabuuchiae, Leptotrichia buccalis, Levilinea saccharolytica, Luteimonas aestuarii, Luteimonas aquatica, Luteimonas composti, Luteimonas lutimaris, Luteimonas marina, Luteimonas mephitis, Luteimonas vadosa, Megamonas, Megasphaera, Meiothermus, Meiothermus timidus, Methylobacterium fujisawaense, Morax-Axenfeld diplobacilli, Moraxella, Moraxella bovis, Moraxella osloensis, Morganella morganii, Mycobacterium, Mycoplasma spumans, Negativicutes, Neisseria cinerea, Neisseria gonorrhoeae, Neisseria meningitidis, Neisseria polysaccharea, Neisseria sicca, Nitrosomonas eutropha, Nitrosomonas halophila, Nitrosomonas oligotropha, Paraburkholderia, Pectinatus, Pedobacter heparinus, Pelosinus, Propionispora, Proteobacteria, Proteus mirabilis, Proteus penneri, Pseudomonas, Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas luteola, Pseudomonas putida, Pseudomonas syringae, Pseudoxanthomonas broegbernensis, Pseudoxanthomonas japonensis, Rickettsia rickettsii, Salinibacter ruber, Salmonella, Salmonella bongori, Salmonella enterica, Samsonia, Selenomonadales, Serratia marcescens, Shewanella algae, Shewanella baltica, Shewanella Shigella, Shigella boydii, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Shimwellia decolorationis, Shewanella frigidmarina, Shewanella gelidimarina, Shewanella halitosis, Shewanella livingstonensis, Shewanella oneidensis, Shewanella putrefaciens, Shewanella sediminis, Shewanella violacea, Shewanella woodyi, Sorangium cellulosum, Sphaerotilus natans, Sphingomonas gei, Spirochaeta, Spirochaetaceae, Sporomusa, Stenotrophomonas, Stenotrophomonas maltophilia, Stenotrophomonas nitritireducens, Thermotoga neapolitana, Thorselliaceae, Vampirococcus, Verminephrobacter, Vibrio adaptatus, Vibrio azasii, Vibrio campbellii, Vibrio casei, Vibrio cholerae, Vibrio coralliiyticus, Vibrio cyclitrophicus, Vibrio diabolicus, Vibrio fluvialis, Vibrio furnissii, Vibrio harveyi, Vibrio mimicus, Vibrio mytili, Vibrio natriegens, Vibrio ordalii, Vibrio parahaemolyticus, Vibrio pectenicida, Vibrio tapetis, Vibrio vulnificus, Victivallis vadensis, Vitreoscilla, Wiggle sw or thia, Wigglesworthia glossinidia, Wolbachia, Yersinia, Yersinia aldovae, Yersinia bercovieri, Yersinia enterocolitica, Yersinia intermedia, Yersinia kristensenii, Yersinia mollaretii, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia ruckeri, Zymophilus.

In certain embodiments, the compounds disclosed herein, such as salmeterol, lomerizine, fendiline, or combinations thereof, can be administered in combination with other antimicrobial or antibiotic agents such as 2,4-DIAMINOPYRIMIDINES, including Baquiloprim, Brodimoprim, Iclaprim, Ormetoprim, Pyrimethamine, Tetroxoprim, Trimethoprim; AMINOCOUMARINS, including Novobiocin; AMINO CYCLITOLS, including Spectinomycin; AMINOGLYCOSIDES, including Amikacin, Apramycin, Arbekacin, Bekanamycin, Butirosin, Dibekacin, Dihydrostreptomycin, Etimicin, Fortimicins, Astromicin, Framycetin, Gentamicin, Hygromycin B, Isepamicin, Kanamycin, Micronomicin, Neomycin, Netilmicin, Paromomycin, Plazomicin, Ribostamycin, Sisomicin, Streptomycin, Tobramycin; AMINOMETHYLCYCLINES, including Omadacycline; AMPHENICOLS, including Azidamfenicol, Chloramphenicol, Florfenicol, Thiamphenicol; ANSAMYCINS, including Rifabutin, Rifampicin, Rifapentine, Rifaximin; ANTITUBERCULAR AGENTS, including Cycloserine, Delamanid, Ethambutol, Ethionamide, Morinamide, p-Aminosalicylic Acid (PAS), Protionamide, Pyrazinamide, Terizidone, Thioacetazone; BACTERIOCINS, including Nisin; B-LACTAM CARBACEPHEMS, including Loracarbef; B-LACTAM CARBAPENEMS, including Biapenem, Doripenem, Ertapenem, Faropenem, Imipenem, Meropenem, Panipenem, Razupenem, Sulopenem, Tebipenem, Tomopenem; B-LACTAM CEPHALOSPORINS, including Cefacetrile, Cefaclor, Cefadroxil, Cefalexin, Cefalonium, Cefaloridine, Cefamandole, Cefapirin, Cefatrizine, Cefazaflur, Cefazedone, Cefazolin, Cefcapene, Cefdinir, Cefditoren, Cefepime, Cefetamet, Cefixime, Cefmenoxime, Cefodizime, Cefonicid, Cefoperazone, Ceforanide, Cefoselis, Cefotaxime, Cefotiam, Cefovecin, Cefozopran, Cefpimizole, Cefpiramide, Cefpirome, Cefpodoxime, Cefprozil, Cefquinome, Cefradine, Cefroxadine, Cefsulodin, Ceftaroline, Ceftazidime, Cefteram, Ceftezole, Ceftibuten, Ceftiofur, Ceftizoxime, Ceftobiprole, Ceftolozane, Ceftriaxone, Cefuroxime, Cefuzonam; B-LACTAM CEPHAMYCINS, including Cefbuperazone, Cefmetazole, Cefotetan, Cefoxitin; B-LACTAM MONOBACTAMS, including Aztreonam, Carumonam, Tigemonam; B-LACTAM OXACEPHEMS, including Flomoxef, Latamoxef, Moxalactam; B-LACTAM PENICILLINS, including Amdinocillin (Mecillinam), Amoxicillin, Ampicillin, Apalcillin, Azidocillin, Azlocillin, Bacampicillin, Carbenicillin, Ciclacillin, Clemizole Penicillin, Cioxacillin, Cyclacillin, Dicloxacillin, Epicillin, Fenbenicillin, Floxacillin (Flucioxacillin), Hetacillin, Mecillinam, Metampicillin, Methicillin Sodium, Mezlocillin, Nafcillin, Oxacillin, Penamecillin, Penethamate Hydriodide, Penicillin G, Penicillin G Benzathine, Penicillin G Procaine, Penicillin N, Penicillin 0, Penicillin V, Phenethicillin Potassium, Piperacillin, Pivampicillin, Pivmecillinam, Propicillin, Quinacillin, Sultamicillin, Talampicillin, Temocillin, Ticarcillin; B-LACTAMS in combination with B-LACTAMASE INHIBITORS, including Avibactam, Clavulanic Acid, Relebactam, Sulbactam, Tazobactam, Vaborbactam, Zidebactam; BICYCLOMYCINS, including Bicozamycin; BIS-BENZIMID AZOLES, including ridinilazole; CYCLIC ESTERS, including Fosfomycin; FLUOROQUINOLONES, including Avarofloxacin, Balofloxacin, Besifloxacin, Cinoxacin, Ciprofloxacin, Clinafloxacin, Danofloxacin, Delafloxacin, Difloxacin, Enoxacin, Enrofloxacin, Finafloxacin, Fleroxacin, Flumequine, Garenoxacin, Gatifloxacin, Gemifloxacin, Grepafloxacin, Levofloxacin, Lomefloxacin, Marbofloxacin, Miloxacin, Moxifloxacin, Nadifloxacin, Norfloxacin, Ofloxacin, Orbifloxacin, Pazufloxacin, Pefloxacin, Pradofloxacin, Prulifloxacin, Rosoxacin, Rufloxacin, Sarafloxacin, Sitafloxacin, Sparfloxacin, Temafloxacin, Tosufloxacin, Trovafloxacin, Zabofloxacin; FUSIDANES, including Fusidic Acid; GLYCOLIPODEPSIPEPTIDE, including Ramoplanin; GLYCOPEPTIDES, including Avoparcin, Dalbavancin, Norvancomycin, Oritavancin, Teicoplanin, Telavancin, Vancomycin; GLYCYLCYCLINES, including Tigecycline; HYBRIDS, Cadazolid (Oxazolidinone-quinolone), TD-1792 (glycopeptidecephalosporin); LINCOSAMIDES, including Clindamycin, Lincomycin, Pirlimycin; LIPOPEPTIDES, including Daptomycin, Surotomycin; MACROLIDES, including Azithromycin, Cethromycin, Clarithromycin, Dirithromycin, Erythromycin, Fidaxomicin, Flurithromycin, Gamithromycin, Josamycin, Kitasamycin, Leucomycin, Miokamycin, Oleandomycin, Primycin, Rokitamycin, Rosaramicin, Roxithromycin, Solithromycin, Spiramycin, Telithromycin, Tildipirosin, Tilmi cosin, Troleandomycin, Tulathromycin, Tylosin, Tylvalosin; NITROFURANS, including Furaltadone, Furazidin, Furazolidone, Nifuroxazide, Nifurtoinol, Nifurzide, Nitrofural, Nitrofurantoin, Nitrofurazone; NITROIMIDAZOLES, including Dimetridazole, Metronidazole, Ornidazole, Ronidazole, Secnidazole, Tinidazole; OLIGOSACCHARIDES, including Avilamycin, Eveminomicin; POLYMYXINS, including Polymyxin E (Colistin), Polymyxin B; POLYPEPTIDES, including Amphomycin, Bacitracin, Capreomycin, Enduracidin, Enramycin, Gramicidin(s), Ristocetin, Tuberactinomycin, Tyrocidine, Tyrothricin, Viomycin; PSEUDOMONIC ACIDS, including Mupirocin; QUINOXALINES, including Carbadox, Olaquindox; RIMINOFENAZINES, including Clofazimine; SIDEROPHORE-LINKED ANTIBIOTICS, including Cefiderocol; STREPTOTHRICINS, including Nourseothricin; SULFONAMIDES, including Acetyl Sulfamethoxypyrazine, Chloramine-B, Chloramine-T, Dichloramine T, Mafenide, N4-Sulfanilylsulfanilamide, N-Sulfanilyl-3,4-xylamide, Sulfacetamide, Sulfadiazine, Sulfadimidine, Sulfamethazine, Sulfamethizole, Sulfapyridine, Sulfathiazole, Sulfisomidine, Sulfisoxazole; SULFONES, including Dapsone, Sodium, Sulfanilic Acid; TETRACYCLINES, including Chlortetracycline, Clomocycline, Demeclocycline, Doxycycline, Lymecycline, Meclocycline, Methacycline, Minocycline, Oxytetracycline, Rolitetracy cline, Tetracycline; TRIAZAACENAPHTHYLENE, including Gepotidacin.

In certain embodiments, this disclosure contemplates pharmaceutical compositions comprising compounds disclosed herein such as salmeterol, lomerizine, and/or fendiline and a pharmaceutically acceptable excipient and optionally another antibacterial agent, e.g., as reported herein. In certain embodiments, compounds disclosed herein such as salmeterol, lomerizine, and/or fendiline are in a pharmaceutical composition in the form of a table, pill, capsule, lotion, or gel. In certain embodiments, compounds disclosed herein such as salmeterol, lomerizine, and/or fendiline are in a pharmaceutical composition in the form of a liquid comprising pH buffering agents and optionally salts and/or saccharide or polysaccharide.

In certain embodiments, the pharmaceutically acceptable excipient is selected from lactose, sucrose, mannitol, triethyl citrate, dextrose, cellulose, methyl cellulose, ethyl cellulose, hydroxyl propyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, croscarmellose sodium, polyvinyl N-pyrrolidone, crospovidone, ethyl cellulose, povidone, methyl and ethyl acrylate copolymer, polyethylene glycol, fatty acid esters of sorbitol, lauryl sulfate, gelatin, glycerin, glyceryl monooleate, silicon dioxide, titanium dioxide, talc, com starch, carnauba wax, stearic acid, sorbic acid, magnesium stearate, calcium stearate, castor oil, mineral oil, calcium phosphate, starch, carboxymethyl ether of starch, iron oxide, triacetin, acacia gum, esters, or salts thereof.

In certain embodiments, the pharmaceutical composition is in the form of a tablet, pill, capsule, powders, granules, gel, gel capsule, or cream. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or: (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders, as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia gum, (c) humectants, as for example, glycerol (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (e) solution retarders, as for example paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example cetyl alcohol, and glycerol monostearate, (h) adsorbents, as for example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof.

Solid dosage forms can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain opacifying agents and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. In certain embodiments, pharmaceutical composition is in solid form surrounded by an enteric coating. In certain embodiments, the enteric coating comprises methyl acrylate-methacrylic acid copolymers, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymers, or combinations thereof.

In certain embodiments, this disclosure contemplates an intravenous formulation with pH buffering agents and tonicity in a range representing physiological values (pH 7 to 8) or for bolus administration, e.g., containing normal saline or dextrose optionally containing pH buffering agents. In certain embodiments, the pharmaceutical composition is in the form of a sterilized pH buffered aqueous salt solution or a saline phosphate buffer between a pH of 6 to 8, optionally comprising a saccharide or polysaccharide.

Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable (such as olive oil, sesame oil) and injectable organic esters such as ethyl oleate.

These compositions may also contain preserving, emulsifying, and dispensing agents. Prevention of the action of microorganisms may be controlled by addition of any of various antibacterial and antifungal agents, example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 -butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances, and the like.

In certain embodiments, pharmaceutical compositions comprising a compound or combination of compounds disclosed herein can be administered to subjects either orally, parenterally (intravenously, intramuscularly, or subcutaneously), intraci sternally, intraperitoneally, intravesically, locally (powders, ointments, or drops), intravaginally, as a buccal or nasal spray, topically to the skin, or rectally.

In certain embodiments, the pharmaceutical compositions are in a form for inhalation. In certain embodiments, the pharmaceutical composition comprises a compound or combination of compounds disclosed herein and a propellant. In certain embodiments, an aerosolizing propellant is compressed air, ethanol, nitrogen, carbon dioxide, nitrous oxide, hydrofluoroalkanes (HF As), or combinations thereof.

In certain embodiments, the disclosure contemplates a pressurized or unpressurized container comprising a compound or combination of compounds disclosed herein. In certain embodiments, the container is a manual pump spray, inhaler, meter-dosed inhaler, dry powder inhaler, nebulizer, vibrating mesh nebulizerjet nebulizer, or ultrasonic wave nebulizer.

In certain embodiments, this disclosure contemplates kits comprising pharmaceutical compositions comprising salmeterol, lomerizine, and/or fendiline and optionally another antibiotic agent in same or separate pharmaceutical composition. The kits may contain a transfer device such a needle, syringe, cannula, capillary tube, pipette, or pipette tip. In certain embodiments, the agents may be contained in a storage container, sealed, or unsealed, such a vial, bottle, ampule, blister pack, or box. In certain embodiments, the kit further comprises written instructions for using the agents for treating and/or preventing a bacterial or other microbial infection in a subject.

In certain embodiments, this disclosure relates to uses of compounds disclosed herein in the production of a medicament for treating bacterial or other microbial infections disclosed herein.

EXAMPLES

Inhibitors of multidrug resistant Acinetobacter baumannii

A high-throughput screen has identified drugs that exhibit previously unknown antibiotic activity. Compounds were screen for the ability to kill A. baumannii. For this screen, an A. baumannii strain was specifically engineered such that had both main RND-type efflux systems (AdeABC, AdeIJK) were inactivated to minimize efflux of drugs, and a surA mutation was added to increase outer membrane permeability. This strain allows one to identification of active agents due to its increased permeability.

Using the above screen, several compounds were identified that exhibited strong antibioticlike activity and inhibited the growth of A. baumannii at a concentration of 100 uM. These agents were not known to be clinically approved as antibiotics. The serendipitous identification of these drugs as antibiotics was facilitated by using double efflux deficient and hyper-permeable mutant strain in the drug screen.

Salmeterol, a bronchial dilator used to treat asthma, did not kill wild-type A. baumannii at concentrations that killed the efflux deficient and hyperpermeable mutant. However, colistin, a currently used antibiotic, can increase the permeability of other drugs, as it disrupts the outer membrane of Gram-negative bacteria. Therefore, colistin was tested at subinhibitory concentrations together with Salmeterol, where a 4-fold increase in susceptibility was observed. In addition, the combination of subinhibitory colistin and salmeterol was strongly bactericidal. Lomerizine was identified to exhibit strong antibiotic-like activity against wild-type A. baumannii. Lomerizine also had antibacterial activity against our hyper-permeable mutant. Lomerizine is a calcium channel blocker in humans and used to treat migraines. This unexpected result prompted us to perform experiment to determine whether Lomerizine has activity against a wild-type A. baumannii strain. The initial activity was low. However, when combined with colistin, lomerizine resulted in a dramatic 32-fold increase in the MIC, where A. baumannii was now killed a concentration of 8 ug/ml of Lomerizine.

Identifying inhibitors of multidrug resistant Acinetobacter baumannii

A library of FDA approved drugs was screened for growth inhibition of Acinetobacter baumannii. Drugs that strongly inhibited the growth of A. baumannii were identified screening at a concentration of 100 micromolar. To conduct this screen, A. baumannii strain was engineered to increase the sensitivity of the assay. This strain had both main RND-type efflux systems (AdeABC, AdeIJK) inactivated to minimize efflux of drugs, and contained a surA mutation to increase outer membrane permeability. The OD values represent bacterial growth after 48 hours. Multiple drugs with activity were identified that were not previously classified as antibiotics.

Lomerizine and Fendiline

The A. baumannii 17978 adeB/adeJ/surA triple mutant strain had a minimum inhibitory concentration (MIC) of 16 g/ml for lomerizine. When tested against a wild-type laboratory strain (17978), the MIC was >256 pg/ml demonstrating the sensitivity of the engineered strain. The addition of subinhibitory concentrations of colistin restored lomerizine killing of a wild-type strain, with a MIC of 8 pg/ml. Lomerizine also killed a clinical isolate of A. baumannii (AB5075). The lomerizine derivative fendiline was 4-fold more potent. Both lomerizine and fendiline had strong antibiotic activity against other Gram-negative pathogens such as Pseudomonas aeruginosa and Enterobacter cloacae indicating lomerizine and fendiline may have broad spectrum activity. Table 1 Minimum inhibitory concentrations (MICs) for lomerizine and fendiline against A. baumannii laboratory (17978) and clinical isolate (AB5075.R7) and other Gram-negative bacterial pathogens (Pseudomonas aeruginosa PA14 and Enterobacter cloacae).

Lomerizine inhibits growth by actively killing A. baumannii. Antibiotics can inhibit growth without killing (bacteriostatic) or with killing (bactericidal). Bactericidal antibiotics are generally preferable. Experiments indication that Lomerizine is bactericidal (Figure 1). Salmeterol

Below is data indicating A. baumannii wild-type cells become sensitized to Salmeterol in the presence of subinhibitory concentrations of colistin.

Claims

1. A method of treating a bacterial infection comprising administering an effective amount of lomerizine to a subject in need thereof.

2. The method of claim 1, wherein the bacterial infection is a gram-negative bacterial infection.

3. The method of claim 1, wherein bacterial infection is multi drug resistant.

4. The method of claim 3, wherein the subject is infected with or diagnosed with Acinetobacter baumannii.

5. The method of claim 1, wherein salmeterol is administered in combination with a cationic antibiotic or a polymyxin.

6. The method of claim 5, wherein the polymyxin is colistin.

7. A method of treating a bacterial infection comprising administering an effective amount of salmeterol to a subject in need thereof.

8. The method of claim 7, wherein the bacterial infection is a gram-negative bacterial infection.

9. The method of claim 8, wherein bacterial infection is multidrug resistant.

10. The method of claim 7, wherein the subject is infected with or diagnosed with Acinetobacter baumannii.

11. The method of claim 7, wherein lomerizine is administered in combination with a cationic antibiotic or a polymyxin.

12. The method of claim 11, wherein the polymyxin is colistin.

13. A method of treating a bacterial infection comprising administering an effective amount of fendiline to a subject in need thereof.

14. The method of claim 13, wherein the bacterial infection is a gram-negative bacterial infection.

15. The method of claim 13, wherein bacterial infection is multidrug resistant.

16. The method of claim 15, wherein the subject is infected with or diagnosed with Acinetobacter baumannii.

17. The method of claim 13, wherein fendiline is administered in combination with a cationic antibiotic or a polymyxin.

18. The method of claim 13, wherein the polymyxin is colistin.