WO2024158908A1 - Méthodes de traitement d'infections bactériennes - Google Patents

Méthodes de traitement d'infections bactériennes Download PDF

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Publication number
WO2024158908A1
WO2024158908A1 PCT/US2024/012775 US2024012775W WO2024158908A1 WO 2024158908 A1 WO2024158908 A1 WO 2024158908A1 US 2024012775 W US2024012775 W US 2024012775W WO 2024158908 A1 WO2024158908 A1 WO 2024158908A1
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Prior art keywords
mycobacterium
legionella
staphylococcus
certain embodiments
bacterial infection
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PCT/US2024/012775
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English (en)
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Philip RATHER
Jennifer COLQUHOUN
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Emory University
U.S. Govenrment Represented By The United States Department Of Veterans Affairs
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Application filed by Emory University, U.S. Govenrment Represented By The United States Department Of Veterans Affairs filed Critical Emory University
Publication of WO2024158908A1 publication Critical patent/WO2024158908A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents

Definitions

  • 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.
  • SARS-CoV-2 viruses
  • the development of antibiotic resistance in A. baumannii has reached a crisis stage. Thus, there is a need to identify improved treatments.
  • 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.
  • the compound is salmeterol, lomerizine, fendiline, or combinations thereof.
  • the bacterial infection is a multidrug resistant gram-negative bacterial infection.
  • 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.
  • another antibiotic such as a cationic antibiotic or a polymyxin such a colistin.
  • 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.
  • this disclosure contemplates kits and pharmaceutical compositions comprising compounds disclosed herein and a pharmaceutically acceptable excipient and optionally another antibacterial agent.
  • 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.
  • CFU colony forming units
  • 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.
  • 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.
  • 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.
  • 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.
  • subject refers to any animal, preferably a human patient, livestock, or domestic pet.
  • 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.
  • 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.
  • 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.
  • the compound is salmeterol, lomerizine, and/or fendiline.
  • the bacterial infection is a multidrug resistant gram-negative bacterial infection, the subject is infected with or diagnosed with Acinetobacter baumcmnii.
  • compounds disclosed herein are administered in combination with a cationic antibiotic or a polymyxin such a colistin.
  • 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.
  • 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.
  • 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).
  • 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.
  • this disclosure contemplates methods and compositions disclosed herein for use in treating a variety of microbial infections using compounds disclosed herein.
  • 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,
  • 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.
  • 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.
  • 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.
  • Streptococcus mitis species group S. cristatus, S. infantis, S. mitis, S. oxalis, S. peroris, S. orisratti
  • 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.
  • Streptococcus salivarius species group S. alactolyticus, S. hyointestinalis, S. infantarius, S. salivarius, S. thermophilus, S.
  • 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
  • the compounds disclosed herein 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, Sisomici
  • 2,4-DIAMINOPYRIMIDINES including Baquiloprim, Brodimoprim, Iclaprim
  • 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.
  • 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.
  • 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.
  • 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
  • the pharmaceutical composition is in the form of a tablet, pill, capsule, powders, granules, gel, gel capsule, or cream.
  • 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,
  • 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.
  • 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.
  • CAP cellulose acetate phthalate
  • PVAP polyvinyl acetate phthalate
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and
  • 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.
  • the pharmaceutical compositions are in a form for inhalation.
  • the pharmaceutical composition comprises a compound or combination of compounds disclosed herein and a propellant.
  • an aerosolizing propellant is compressed air, ethanol, nitrogen, carbon dioxide, nitrous oxide, hydrofluoroalkanes (HF As), or combinations thereof.
  • the disclosure contemplates a pressurized or unpressurized container comprising a compound or combination of compounds disclosed herein.
  • the container is a manual pump spray, inhaler, meter-dosed inhaler, dry powder inhaler, nebulizer, vibrating mesh nebulizerjet nebulizer, or ultrasonic wave nebulizer.
  • 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.
  • the agents may be contained in a storage container, sealed, or unsealed, such a vial, bottle, ampule, blister pack, or box.
  • the kit further comprises written instructions for using the agents for treating and/or preventing a bacterial or other microbial infection in a subject.
  • this disclosure relates to uses of compounds disclosed herein in the production of a medicament for treating bacterial or other microbial infections disclosed herein.
  • a high-throughput screen has identified drugs that exhibit previously unknown antibiotic activity. Compounds were screen for the ability to kill A. baumannii.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the A. baumannii 17978 adeB/adeJ/surA triple mutant strain had a minimum inhibitory concentration (MIC) of 16 g/ml for lomerizine.
  • MIC minimum inhibitory concentration
  • 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.
  • 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

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Abstract

La présente divulgation concerne des méthodes de traitement d'une infection bactérienne consistant à administrer une quantité efficace d'un composé ou de composés identifiés dans la description à un sujet en ayant besoin. Dans certains modes de réalisation, le composé est du salmétérol, de la lomerizine et/ou de la fendiline. Dans certains modes de réalisation, l'infection bactérienne est une infection bactérienne résistante à plusieurs médicaments. Dans certains modes de réalisation, le sujet est infecté par une infection Acinetobacter baumannii ou diagnostiqué comme étant atteint de celle-ci. Dans certains modes de réalisation, des composés divulgués dans la description sont administrés en combinaison avec un antibiotique cationique ou une polymyxine telle qu'une colistine.
PCT/US2024/012775 2023-01-24 2024-01-24 Méthodes de traitement d'infections bactériennes WO2024158908A1 (fr)

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