Discovery of multidrug efflux pump inhibitors with a novel chemical scaffold

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

doi:10.1016/j.bbagen.2020.129546

Discovery of multidrug efflux pump inhibitors with a novel chemical scaffold

Biochim Biophys Acta Gen Subj. 2020 Jun;1864(6):129546. doi: 10.1016/j.bbagen.2020.129546. Epub 2020 Feb 4.

Authors

Adam T Green¹, Mohammad Moniruzzaman², Connor J Cooper¹, John K Walker³, Jeremy C Smith⁴, Jerry M Parks⁵, Helen I Zgurskaya⁶

Affiliations

¹ UT/ORNL Center for Molecular Biophysics, Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA; Graduate School of Genome Science and Technology, University of Tennessee, Knoxville, TN, 37996, USA.
² Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, USA.
³ Department of Pharmacology and Physiology, Saint Louis University School of Medicine and the Henry and Amelia Nasrallah Center for Neuroscience, Saint Louis, MO, 63104, USA.
⁴ UT/ORNL Center for Molecular Biophysics, Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA; Graduate School of Genome Science and Technology, University of Tennessee, Knoxville, TN, 37996, USA; Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, TN 37996, USA.
⁵ UT/ORNL Center for Molecular Biophysics, Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA; Graduate School of Genome Science and Technology, University of Tennessee, Knoxville, TN, 37996, USA. Electronic address: parksjm@ornl.gov.
⁶ Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, USA. Electronic address: elenaz@ou.edu.

Abstract

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.

Keywords: Docking; Gram-negative; Minimum inhibitory concentration; Permeability; Resistance nodulation division; Substrate.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Acinetobacter baumannii / drug effects
Acinetobacter baumannii / pathogenicity
Anti-Bacterial Agents / adverse effects
Anti-Bacterial Agents / pharmacology
Anti-Infective Agents / chemistry
Anti-Infective Agents / pharmacology*
Carrier Proteins / antagonists & inhibitors
Carrier Proteins / chemistry*
Computational Biology / methods
Drug Resistance, Bacterial / drug effects
Drug Resistance, Bacterial / genetics
Drug Synergism
Erythromycin / chemistry
Erythromycin / pharmacology
Escherichia coli Proteins / antagonists & inhibitors
Escherichia coli Proteins / chemistry*
Gram-Negative Bacteria / drug effects
Gram-Negative Bacteria / pathogenicity
Gram-Negative Bacterial Infections / drug therapy*
Gram-Negative Bacterial Infections / microbiology
Gram-Negative Bacterial Infections / pathology
Humans
Klebsiella pneumoniae
Lipoproteins / antagonists & inhibitors
Lipoproteins / chemistry*
Membrane Transport Proteins / chemistry*
Molecular Docking Simulation
Multidrug Resistance-Associated Proteins / antagonists & inhibitors
Multidrug Resistance-Associated Proteins / chemistry*
Novobiocin / chemistry
Novobiocin / pharmacology

Substances

AcrA protein, E coli
AcrAB-TolC protein, E coli
AcrB protein, E coli
Anti-Bacterial Agents
Anti-Infective Agents
Carrier Proteins
Escherichia coli Proteins
Lipoproteins
Membrane Transport Proteins
Multidrug Resistance-Associated Proteins
Novobiocin
Erythromycin

Abstract

Publication types

MeSH terms

Substances

Grants and funding