TY - JOUR
T1 - Two-Way Regulation of MmpL3 Expression Identifies and Validates Inhibitors of MmpL3 Function in Mycobacterium tuberculosis
AU - Grover, Shipra
AU - Engelhart, Curtis A
AU - Pérez-Herrán, Esther
AU - Li, Wei
AU - Abrahams, Katherine A
AU - Papavinasasundaram, Kadamba
AU - Bean, James M
AU - Sassetti, Christopher M
AU - Mendoza-Losana, Alfonso
AU - Besra, Gurdyal S
AU - Jackson, Mary
AU - Schnappinger, Dirk
PY - 2020/12/15
Y1 - 2020/12/15
N2 - 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.
AB - 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.
U2 - 10.1021/acsinfecdis.0c00675
DO - 10.1021/acsinfecdis.0c00675
M3 - Article
C2 - 33319550
SN - 2373-8227
JO - ACS Infectious Diseases
JF - ACS Infectious Diseases
ER -