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Type: Journal article
Title: Structural optimization of natural product nordihydroguaretic acid to discover novel analogues as AcrB inhibitors
Author: Wang, Y.
Alenzy, R.
Song, D.
Liu, X.
Teng, Y.
Mowla, R.
Ma, Y.
Polyak, S.W.
Venter, H.
Ma, S.
Citation: European Journal of Medicinal Chemistry, 2020; 186
Publisher: Elsevier
Issue Date: 2020
ISSN: 0223-5234
Statement of
Yinhu Wang, Rawaf Alenzy, Di Song, Xingbang Liu, Yuetai Teng ... Steven W. Polyak ... et al.
Abstract: Drug efflux pumps confer multidrug resistance to dangerous bacterial pathogens which makes these proteins promising drug targets. Herein, we present initial chemical optimization and structure-activity relationship (SAR) data around a previously described efflux pump inhibitor, nordihydroguaretic acid (NDGA). Four series of novel NDGA analogues that target Escherichia coli AcrB were designed, synthesized and evaluated for their ability to potentiate the activity of antibiotics, to inhibit AcrB-mediated substrate efflux and reduce off-target activity. Nine novel structures were identified that increased the efficacy of a panel of antibiotics, inhibited drug efflux and reduced permeabilization of the bacterial outer and inner membranes. Among them, WA7, WB11 and WD6 possessing broad-spectrum antimicrobial sensitization activity were identified as NDGA analogues with favorable properties as potential AcrB inhibitors, demonstrating moderate improvement in potency as compared to NDGA. In particular, WD6 was the most broadly active analogue improving the activity of all four classes of antibacterials tested.
Keywords: AcrB inhibitors; Efflux pump; Multidrug resistance; Nordihydroguaretic acid; Structural optimization
Rights: © 2019 Elsevier Masson SAS. All rights reserved.
RMID: 1000011148
DOI: 10.1016/j.ejmech.2019.111910
Grant ID:
Appears in Collections:Molecular and Biomedical Science publications

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