Two-Way Regulation of MmpL3 Expression Identifies and Validates Inhibitors of MmpL3 Function in Mycobacterium tuberculosis
Authors
Grover, ShipraEngelhart, Curtis A.
Perez-Herran, Esther
Li, Wei
Abrahams, Katherine A.
Papavinasasundaram, Kadamba
Bean, James M.
Sassetti, Christopher M.
Mendoza-Losana, Alfonso
Besra, Gurdyal S.
Jackson, Mary
Schnappinger, Dirk
UMass Chan Affiliations
Department of Microbiology and Physiological SystemsDocument Type
Journal ArticlePublication Date
2021-01-08Keywords
antibioticsdrug discovery
molecular genetics
mycolic acids
respiration
targeted whole-cell screen
Bacterial Infections and Mycoses
Medicinal-Pharmaceutical Chemistry
Microbiology
Pharmacy and Pharmaceutical Sciences
Metadata
Show full item recordAbstract
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.Source
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
DOI
10.1021/acsinfecdis.0c00675Permanent Link to this Item
http://hdl.handle.net/20.500.14038/41694PubMed ID
33319550Related Resources
Rights
Copyright © 2020 American Chemical Society. This is an open access article published under a Creative Commons Non-Commercial No Derivative Works (CC-BY-NC-ND) Attribution License, which permits copying and redistribution of the article, and creation of adaptations, all for non-commercial purposes.Distribution License
http://creativecommons.org/licenses/by-nc-nd/4.0/ae974a485f413a2113503eed53cd6c53
10.1021/acsinfecdis.0c00675
Scopus Count
Collections
Except where otherwise noted, this item's license is described as Copyright © 2020 American Chemical Society. This is an open access article published under a Creative Commons Non-Commercial No Derivative Works (CC-BY-NC-ND) Attribution License, which permits copying and redistribution of the article, and creation of adaptations, all for non-commercial purposes.