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Two-Way Regulation of MmpL3 Expression Identifies and Validates Inhibitors of MmpL3 Function in Mycobacterium tuberculosis.

Abstract：

:MmpL3, an essential mycolate transporter in the inner membrane of Mycobacterium tuberculosis (Mtb), has been identified as a target of multiple, chemically diverse antitubercular drugs. However, several of these molecules seem to have secondary targets and inhibit bacterial growth by more than one mechanism. Here, we describe a cell-based assay that utilizes two-way regulation of MmpL3 expression to readily identify MmpL3-specific inhibitors. We successfully used this assay to identify a novel guanidine-based MmpL3 inhibitor from a library of 220 compounds that inhibit growth of Mtb by largely unknown mechanisms. We furthermore identified inhibitors of cytochrome bc 1 -aa 3 oxidase as one class of off-target hits in whole-cell screens for MmpL3 inhibitors and report a novel sulfanylacetamide as a potential QcrB inhibitor.

journal_name

ACS Infect Dis

journal_title

ACS infectious diseases

authors

Grover S,Engelhart CA,Pérez-Herrán E,Li W,Abrahams KA,Papavinasasundaram K,Bean JM,Sassetti CM,Mendoza-Losana A,Besra GS,Jackson M,Schnappinger D

doi

10.1021/acsinfecdis.0c00675

subject

Has Abstract

pub_date

2021-01-08 00:00:00

pages

141-152

issue

1

issn

2373-8227

journal_volume

7

pub_type

杂志文章

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