Discovery of multidrug efflux pump inhibitors with a novel chemical scaffold.
Acinetobacter baumannii
/ drug effects
Anti-Bacterial Agents
/ adverse effects
Anti-Infective Agents
/ chemistry
Carrier Proteins
/ antagonists & inhibitors
Computational Biology
/ methods
Drug Resistance, Bacterial
/ drug effects
Drug Synergism
Erythromycin
/ chemistry
Escherichia coli Proteins
/ antagonists & inhibitors
Gram-Negative Bacteria
/ drug effects
Gram-Negative Bacterial Infections
/ drug therapy
Humans
Klebsiella pneumoniae
Lipoproteins
/ antagonists & inhibitors
Membrane Transport Proteins
/ chemistry
Molecular Docking Simulation
Multidrug Resistance-Associated Proteins
/ antagonists & inhibitors
Novobiocin
/ chemistry
Docking
Gram-negative
Minimum inhibitory concentration
Permeability
Resistance nodulation division
Substrate
Journal
Biochimica et biophysica acta. General subjects
ISSN: 1872-8006
Titre abrégé: Biochim Biophys Acta Gen Subj
Pays: Netherlands
ID NLM: 101731726
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
25
11
2019
revised:
21
01
2020
accepted:
30
01
2020
pubmed:
8
2
2020
medline:
23
10
2020
entrez:
8
2
2020
Statut:
ppublish
Résumé
Multidrug efflux is a major contributor to antibiotic resistance in Gram-negative bacterial pathogens. Inhibition of multidrug efflux pumps is a promising approach for reviving the efficacy of existing antibiotics. Previously, inhibitors targeting both the efflux transporter AcrB and the membrane fusion protein AcrA in the Escherichia coli AcrAB-TolC efflux pump were identified. Here we use existing physicochemical property guidelines to generate a filtered library of compounds for computational docking. We then experimentally test the top candidate coumpounds using in vitro binding assays and in vivo potentiation assays in bacterial strains with controllable permeability barriers. We thus identify a new class of inhibitors of E. coli AcrAB-TolC. Six molecules with a shared scaffold were found to potentiate the antimicrobial activity of erythromycin and novobiocin in hyperporinated E. coli cells. Importantly, these six molecules were also active in wild-type strains of both Acinetobacter baumannii and Klebsiella pneumoniae, potentiating the activity of erythromycin and novobiocin up to 8-fold.
Identifiants
pubmed: 32032658
pii: S0304-4165(20)30036-2
doi: 10.1016/j.bbagen.2020.129546
pmc: PMC7153915
mid: NIHMS1570345
pii:
doi:
Substances chimiques
AcrA protein, E coli
0
AcrAB-TolC protein, E coli
0
AcrB protein, E coli
0
Anti-Bacterial Agents
0
Anti-Infective Agents
0
Carrier Proteins
0
Escherichia coli Proteins
0
Lipoproteins
0
Membrane Transport Proteins
0
Multidrug Resistance-Associated Proteins
0
Novobiocin
17EC19951N
Erythromycin
63937KV33D
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
129546Subventions
Organisme : NIAID NIH HHS
ID : R01 AI052293
Pays : United States
Organisme : NIAID NIH HHS
ID : R56 AI052293
Pays : United States
Organisme : NIH HHS
ID : S10 OD025014
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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