Two-Way Regulation of MmpL3 Expression Identifies and Validates Inhibitors of MmpL3 Function in Mycobacterium tuberculosis
Engelhart, Curtis A.
Abrahams, Katherine A.
Bean, James M.
Sassetti, Christopher M.
Besra, Gurdyal S.
UMass Chan AffiliationsDepartment of Microbiology and Physiological Systems
Document TypeJournal Article
targeted whole-cell screen
Bacterial Infections and Mycoses
Pharmacy and Pharmaceutical Sciences
MetadataShow full item record
AbstractMmpL3, 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.
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. Two-Way Regulation of MmpL3 Expression Identifies and Validates Inhibitors of MmpL3 Function in Mycobacterium tuberculosis. ACS Infect Dis. 2021 Jan 8;7(1):141-152. doi: 10.1021/acsinfecdis.0c00675. Epub 2020 Dec 15. PMID: 33319550; PMCID: PMC7802072. Link to article on publisher's site