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

Overview

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 bc1-aa3 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.

publication date

  • December 15, 2020

Research

keywords

  • Bacterial Proteins
  • Membrane Transport Proteins
  • Mycobacterium tuberculosis

Identity

PubMed Central ID

  • PMC7802072

Scopus Document Identifier

  • 85099035622

Digital Object Identifier (DOI)

  • 10.1038/ng.806

PubMed ID

  • 33319550

Additional Document Info

volume

  • 7

issue

  • 1