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WO2022153045A1 - Procédés et compositions pour la potentialisation d'antibiotiques - Google Patents

Procédés et compositions pour la potentialisation d'antibiotiques Download PDF

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Publication number
WO2022153045A1
WO2022153045A1 PCT/GB2022/050060 GB2022050060W WO2022153045A1 WO 2022153045 A1 WO2022153045 A1 WO 2022153045A1 GB 2022050060 W GB2022050060 W GB 2022050060W WO 2022153045 A1 WO2022153045 A1 WO 2022153045A1
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Prior art keywords
compounds
antibiotics
lactam antibiotic
meropenem
cwd
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Quadram Institute Bioscience
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Quadram Institute Bioscience
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/191—Carboxylic acids, e.g. valproic acid having two or more hydroxy groups, e.g. gluconic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/345—Nitrofurans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/665—Phosphorus compounds having oxygen as a ring hetero atom, e.g. fosfomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
    • 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

Definitions

  • the present invention relates to the provision of one or more substances for the potentiation or improved efficacy of antibiotics and other compounds or compositions.
  • AMR antimicrobial resistance
  • MDR multi-drug resistant
  • XDR extremely drug resistant
  • PDR pan-drug resistant
  • MDR Gram negative bacteria with resistance to third generation cepholosporins and carbapenems.
  • carbapenem resistant A. baumanii, carbapenem resistant P. aeruginosa and ESBL-producing Enterobacteriaceae including Klebsiella, Escherichia, Serratia and Proteus spp
  • Priority 1 Critical
  • Priority 1 Critical
  • the mechanisms of antibiotic resistance in bacteria include drug inactivation, modification of the target site, increased drug efflux, reduced cell wall permeability, biofilms, and persister cells.
  • the outer-membrane (OM) of Gram negative bacteria poses a significant permeability barrier to many antibiotics which, to enter the cell, must either diffuse across the OM or enter via porins in the OM. Modification of OM permeability through alteration of lipid or porin composition confers elevated antibiotic resistance (Mulani et al. 2019) .
  • the Gram negative bacterium P. aeruginosa is able to tolerate high concentrations of ⁇ -lactam antibiotics, which despite apparently inhibiting the growth of the organism, exhibit remarkably little bactericidal activity (Monahan et al. 2014) .
  • ⁇ -lactam antibiotics carbenicillin, meropenem and imipenem
  • CWD translucent cell wall deficient
  • a method of potentiating or inducing antibiotic efficacy in one or more compositions or compounds including the step of inducing a substantially cell wall deficient (CWD) state in a bacteria by exposure to at least one antibiotic before and/or in combination with said one or more compositions or compounds.
  • CWD substantially cell wall deficient
  • compositions or compounds are antibiotics and/or antimicrobial compounds.
  • the bacteria is a Gram negative species.
  • the one or more antibiotics that induce the CWD state are ⁇ (beta) -lactam antibiotics.
  • the ⁇ -lactam antibiotic is from the carbapenem family.
  • the ⁇ -lactam antibiotic includes meropenem.
  • the ⁇ -lactam antibiotic is delivered in supra- minimum inhibitory concentration (MIC) levels.
  • the compounds or compositions include antibiotics or antimicrobial compounds.
  • antibiotics are from the fluoroquinolone, aminoglycoside, tetracycline, polymixin, clofoctol, macrolide, pleuromutilin, quinolone, amphenicol, rifamycin, fosfomycin tromethamine and/or nitroxoline classes or families of compounds.
  • compositions or compounds include any one or any combination of the antibiotics listed in Table 1 below.
  • the compounds or compositions include antibiotics or antimicrobial compounds, typically the antibiotics are from the nitrofuran, penicillin, glycopeptide, fluoroquinolone, aminocyclitol, fusidate sodium, puromycin hydrochloride, lincosamide, cephalosporin, aminocoumarin, trimethoprim, daptomycin, sulfonamide, carbapenem, clofazimine, capreomycin sulfate, mupirocin, oxazolidinone, nitroimidazole, acetohydroxamic acid, dapsone, sodium sulfadiazine, methenamine, sodium 4-aminosalicylate, bacitracin and/or monobactam classes or families of compounds.
  • antibiotics are from the nitrofuran, penicillin, glycopeptide, fluoroquinolone, aminocyclitol, fusidate sodium, puromycin hydrochloride, lincosamide, cephalosporin, aminocou
  • compositions or compounds include any one or any combination of the antibiotics listed in Table 2 below.
  • compositions or compounds include drugs or approved medications that are not formally recognised as antibiotic or antimicrobial compounds for human or animal use.
  • compositions or compounds include any one or any combination from Table 3 below.
  • the method is used to treat infection by the ‘ESKAPE’ group of pathogens.
  • the ESKAPE group includes — Enterococcus f aecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanni, Pseudomonas aeruginosa and Enterobacter species
  • the infection treated is a P. aeruginosa infection.
  • ⁇ -lactam antibiotic for use in the potentiation of one or more compounds or compositions to treat microbial infections.
  • the ⁇ -lactam antibiotic is provided in a supra- minimum inhibitory concentration (MIC) level. Further typically the ⁇ -lactam is a carbapenem.
  • MIC supra- minimum inhibitory concentration
  • the ⁇ -lactam antibiotic is delivered in a pharmaceutically acceptable carrier.
  • the ⁇ -lactam antibiotic is delivered in a concentration to induce the target bacteria to transition to a CWD state.
  • the CWD state was induced with substantially at least 1 ⁇ g/ml meropenem.
  • 5 ⁇ g/ml meropenem (5x MIC) was used to achieve CWD state in the bacteria.
  • the meropenem sensitive P. aeruginosa strain PA14 was used to identify antibiotics and novel compounds with bactericidal activity against CWD P. aeruginosa. Broth microdilution was used to determine the MIC of meropenem for this strain and was found to be 1 ⁇ g/ml. The concentration of meropenem used to induce P. aeruginosa PA14 to transition to the CWD state was 5 ⁇ g/ ml meropenem (5x MIC) .
  • LB low-salt Lysogeny Broth
  • Agar 5 g/L yeast extract, 5 g/L sodium chloride, 10 g/L tryptone, 15 g/L bacteriological agar; all Oxoid, Cheshire, UK
  • All broth cultures were performed in cation adjusted Mueller Hinton II Broth (CaMHB), prepared as per the manufacturer’s instructions (BD BBLTM, Franklin Lakes, NJ) and grown well aerated at 37 °C, shaking at 250 r.p.m overnight.
  • the Sellekchem FDA Approved Small Chemical Compound Library (Sellekchem, Houstan, TX) was supplied at a concentration of 10 mM dissolved in either DMSO or water and stored at -80 °C and thawed prior to use.
  • a log phase culture was prepared from an overnight broth of the strain diluted 1 : 500 in CaMHB supplemented with 0.5 M sucrose to an OD600nm and grown well-aerated at 37 °C shaking at 250 r.p.m. for 2 hr.
  • Each plate had duplicate wells with 2.5% DMSO; 5 ⁇ g/ml meropenem and 2.5% DMSO; and, 5 ⁇ g/ml meropenem, 2.5% DMSO and 64 ⁇ g/ml of the antimicrobial peptide nisin (Sigma-Aldrich) was included.
  • Nisin was included as a control for CWD bactericidal activity we have previously shown that this antimicrobial peptide is bactericidal only to CWD P. aeruginosa (Monahan et al. 2014) .
  • the plates were shaken briefly, and then incubated statically at 37 °C for 16 hr before the fluorescence was measured at 530/590 ex/em on an Infinite 200 Pro plate reader (TeCan, Mannedorf, Switzerland) .
  • MMAC Minimum Metabolic Activity Concentration
  • aeruginosa cells A CWD bactericidal control of 5 ⁇ g/ml meropenem and 64 ⁇ g/ml nisin was also included.
  • the plates were sealed with semi-permeable membrane and grown without shaking for 20 hr after which resazurin was added to a final concentration of 0.145 ⁇ g/well and the plate was incubated for a further 4 hr without shaking.
  • the fluorescence was read at 530/590 ex/em on a fluorescent plate reader. The values were corrected for the blank and then normalised to the appropriate no-meropenem vehicle control.
  • the minimum metabolic inhibitory concentration was the concentration at which a normalised value of ⁇ 2% was achieved.
  • Resazurin is a non-toxic, weakly fluorescent compound that is reduced by cellular dehydrogenases to the highly fluorescent compound rezarufin and is used to assess metabolic activity as a measure of cell viability ((Sarker et al. 2007), Methods).
  • 146 unique antibiotics from an FDA- Approved Small Chemical Compound library were screened at 250 mM to identify those that showed inhibition of metabolic activity of P.
  • aeruginosa strain PA14 in the presence of 5 ⁇ g/ ml meropenem (5x MIC) .
  • 5x MIC 5 ⁇ g/ ml meropenem
  • 46 antibiotics inhibited metabolic activity by at least 50% when normalised to the meropenem-only control (Supplementary Table 1) .
  • Broth microdilution assays (2-fold dilution series from 125 mM - 0.49 mM) were performed to determine the MMACs in the absence (MMACo) and presence of 5 ⁇ g/ml meropenem (MMACMER) .
  • the potentiation coefficient (MMACO/MMACMER) was calculated for each antibiotic (Table 1) .
  • a potentiation coefficient of 2 or greater indicates that the antibiotic reached our metabolic activity inhibition threshold at a lower concentration in the presence of meropenem than when used without meropenem.
  • antibiotics were: flumequine; streptomycin sulphate; azithromycin dihydrate; demeclocycline hydrochloride; paromomycin sulphate; clarithromycin; hygromycin B; minocycline hydrochloride;erythromycin ethylsuccinate, clofoctal; and valnemulin (Table 1).
  • Macrolides have shown synergistic effects in combination with outer membrane disrupting agents (Buyck et al. 2012) and this is supported by the evidence that the three macrolides were present in our potentiate screen.
  • azithromycin seems to have a greater inhibitory effect than clarithromycin, which in turn has a greater effect than erythromycin (Howe and Spencer 1997) and those findings are in line with our findings which show the macrolides have a MMAC with meropenem of 31.25, 62.5 and 125 respectively (Table 1) which is below the peak serum concentrations from an oral dosing regimen (Foulds et al. 1990; Fraschini et al. 1993; Shanson et al. 1984).
  • Macrolides are bacteriostatic antibiotics that target protein synthesis and include erythromycin, clarithromycin and azithromycin. They are routinely used in the treatment of P. aeruginosa infections despite P. aeruginosa having intrinsic resistance mechanisms to the macrolide antibiotics (Buyck et al. 2012) . This could be due to macrolide alteration of quorum sensing, virulence factor expression, biofilm formation, serum sensitivity and outer membrane integrity (Gillis and Iglewski 2004; Tateda et al. 1996; Tateda et al.
  • Clofoctol is synthetic phenol derivative that is used predominately in France and Italy for the treatment of upper respiratory tract infections by Gram-positive organisms (Danesi and Del Tacca 1985)The mechanism of action against targeted organisms appears to be through a disruption of the permeability of the inner cell membrane leading to collapse of the proton gradient and a decrease in the intracellular pool of ATP required for peptidoglycan synthesis and other enzymatic processes (Yablonsky 1983). The MIC range of clofoctol for susceptible organisms is between 0.3-10 pg/ml (Alessandri et al. 1986; Scaglione et al. 2018).
  • clofoctal has an MMAC of 15.63 pM (Table 1) or 5.7 pg/ml which is comparable to other organisms and a concentration therapeutically relevant.
  • Tioconazole another antimycotic imadazole derivative was identified in our screen with an MMACMER of 31.25 mM (Table 2). Both anti-mycotics are poorly absorbed from the gut and oral administration of clotrimazole resulted in serum levels less than 0.5 ⁇ M (Brugnara et al. 1996) . However, advances in delivery technologies of hydrophobic anti-mycotics to the lung has resulted in concentrations that could prove effective in the future (McConville et al. 2006) .
  • Valnemulin belongs to the pleuromutilin class of antibiotics which have been used in veterinary applications since 1979 with valnemulin being approved for veterinary use in 1999 (Paukner and Riedl 2017). Pleuromutilins work by inhibiting bacterial protein synthesis through binding to the ribosome and are reported to have activity against Gram positive bacteria and Mycoplasmas but no reported activity against P. aeruginosa (Poulsen et al. 2001). In a study of three patients with primary antibody deficiency who had developed a Mycoplasma sepsis, valnemulin was shown to be effective (Heilmann et al. 2001) .
  • aminoglycosides are one of the most frequently used classes of antibiotic in the treatment of P. aeruginosa and, due to this, resistance is frequently encountered ((Poole 2005). Aminoglycosides act by irreversibly binding to the ribosome of bacteria. The combinatorial effects of ⁇ -lactam antibiotics and aminoglycosides have been well established in vitro (Weiss and Lapointe 1995; Nakamura et al. 2000; Tam et al.
  • 8 compounds have uses as antimicrobial agents, either as antimycotics (clotrimazole, tioconazole, and ketoconazole), antivirals (efavirenz, lomibuvir, elvitegravir), antiprotozoals (diclurazil) or biocides (triclosan) .
  • 6 compounds exhibit effects on the central nervous system through interaction with the serotonin and dopamine receptors and have been used as antipsychotics (thioridazine, pimavanserin, mesoridazine besylate, and trifluoperazine hydrochloride), antidepressants (sertraline hydrochloride), or a treatment for Alzheimer’s disease (tacrine hydrochloride).

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé pour potentialiser ou induire une efficacité antibiotique chez un(e) ou plusieurs compositions ou composés, ledit procédé comprenant l'étape consistant à induire un état sensiblement de déficience de paroi cellulaire (CWD) dans une bactérie par exposition à au moins un antibiotique avant et/ou en combinaison avec ladite ou lesdites compositions ou ledit ou lesdits composés.
PCT/GB2022/050060 2021-01-12 2022-01-12 Procédés et compositions pour la potentialisation d'antibiotiques Ceased WO2022153045A1 (fr)

Applications Claiming Priority (2)

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GB2100378.5 2021-01-12
GBGB2100378.5A GB202100378D0 (en) 2021-01-12 2021-01-12 Methods and compositions for antibiotic potentiation

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WO2022153045A1 true WO2022153045A1 (fr) 2022-07-21

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115721722A (zh) * 2022-11-09 2023-03-03 浙江大学 一种治疗egfr-tki耐药的非小细胞肺癌的药物组合物
CN116139132A (zh) * 2022-12-16 2023-05-23 华南农业大学 酚妥拉明作为利福平抗菌增效剂的应用
CN116211852A (zh) * 2022-12-16 2023-06-06 华南农业大学 一种大环内酯类抗生素的增效剂及其应用
CN116763767A (zh) * 2023-06-15 2023-09-19 河南农业大学 姜黄素在增强替加环素抗菌作用中的新用途
CN116785280A (zh) * 2023-07-21 2023-09-22 大连医科大学附属第一医院 orantinib在制备抗生素增强剂中的应用
CN117064881A (zh) * 2023-09-27 2023-11-17 南京农业大学 硝唑尼特在制备抗mcr-1和ndm-5阳性菌株增效剂中的应用
CN118304316A (zh) * 2024-03-29 2024-07-09 华南农业大学 克拉屈滨在制备抑制多重耐药肺炎克雷伯菌生长药物中的应用
WO2024179532A1 (fr) * 2023-02-28 2024-09-06 华东理工大学 Composé actif antibactérien et synergique et son utilisation

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WO2017008034A1 (fr) * 2015-07-09 2017-01-12 Washington University Compositions et méthodes d'utilisation de combinaisons de médicaments antibactériens

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