Discovery of multidrug efflux pump inhibitors with a novel chemical scaffold

Green, Adam T.; Moniruzzaman, Mohammad; Cooper, Connor J.; Walker, John; Smith, Jeremy C.; Parks, Jerry M.; Zgurskaya, Helen I.

doi:10.1016/j.bbagen.2020.129546

Discovery of multidrug efflux pump inhibitors with a novel chemical scaffold

Journal Article · Mon Feb 03 23:00:00 EST 2020 · Biochimica et Biophysica Acta - General Subjects

DOI:https://doi.org/10.1016/j.bbagen.2020.129546· OSTI ID:1606783

Green, Adam T. ^[1]; Moniruzzaman, Mohammad ^[2]; Cooper, Connor J. ^[1]; Walker, John ^[3]; ^[1]; ^[1]; Zgurskaya, Helen I. ^[2]

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.

View Accepted Manuscript (DOE)

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

OSTI ID:: 1606783

Alternate ID(s):: OSTI ID: 1601523

Journal Information:: Biochimica et Biophysica Acta - General Subjects, Journal Name: Biochimica et Biophysica Acta - General Subjects Journal Issue: 6 Vol. 1864; ISSN 0304-4165

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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