Two-Way Regulation of MmpL3 Expression Identifies and Validates Inhibitors of MmpL3 Function in Mycobacterium tuberculosis
Research output: Contribution to journal › Article › peer-review
- 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.
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||ACS Infectious Diseases|
|Publication status||E-pub ahead of print - 15 Dec 2020|