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

Research output: Contribution to journalArticlepeer-review

Authors

  • Shipra Grover
  • Curtis A Engelhart
  • Esther Pérez-Herrán
  • Wei Li
  • Kadamba Papavinasasundaram
  • James M Bean
  • Christopher M Sassetti
  • Alfonso Mendoza-Losana
  • Mary Jackson
  • Dirk Schnappinger

External organisations

  • Harvard Medical School
  • On behalf of the NIHR Global Health Research Unit on Lung Health and TB in Africa (IMPALA).
  • Colorado State University
  • School of Biological Sciences
  • University of Massachusetts Medical School
  • Sloan-Kettering Institute, 1275 York Avenue, Box 252, New York, New York 10065, USA.

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.

Details

Original languageEnglish
JournalACS Infectious Diseases
Publication statusE-pub ahead of print - 15 Dec 2020