Discovery of multidrug efflux pump inhibitors with a novel chemical scaffold
- Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Univ. of Tennessee, Knoxville, TN (United States)
- Univ. of Oklahoma, Norman, OK (United States)
- Saint Louis University, Missouri
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. In this work 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.
- Research Organization:
- Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
- Sponsoring Organization:
- USDOE; National Institutes of Health (NIH); National Science Foundation (NSF); Oklahoma Medical Research Foundation
- Grant/Contract Number:
- AC05-00OR22725; AI052293; 2017219379; S10 OD025014
- OSTI ID:
- 1606783
- Alternate ID(s):
- OSTI ID: 1601523
- Journal Information:
- Biochimica et Biophysica Acta - General Subjects, Vol. 1864, Issue 6; ISSN 0304-4165
- Publisher:
- ElsevierCopyright Statement
- Country of Publication:
- United States
- Language:
- English
Web of Science
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