UMMS Affiliation
Department of Microbiology and Physiological Systems
Publication Date
2021-01-08
Document Type
Article
Disciplines
Bacterial Infections and Mycoses | Medicinal-Pharmaceutical Chemistry | Microbiology | Pharmacy and Pharmaceutical Sciences
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 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.
Keywords
antibiotics, drug discovery, molecular genetics, mycolic acids, respiration, targeted whole-cell screen
Rights and Permissions
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.
DOI of Published Version
10.1021/acsinfecdis.0c00675
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
Journal/Book/Conference Title
ACS infectious diseases
Related Resources
PubMed ID
33319550
Repository Citation
Grover S, Engelhart CA, Perez-Herran E, Li W, Abrahams KA, Papavinasasundaram K, Bean JM, Sassetti CM, Mendoza-Losana A, Besra GS, Jackson M, Schnappinger D. (2021). Two-Way Regulation of MmpL3 Expression Identifies and Validates Inhibitors of MmpL3 Function in Mycobacterium tuberculosis. Open Access Publications by UMMS Authors. https://doi.org/10.1021/acsinfecdis.0c00675. Retrieved from https://escholarship.umassmed.edu/oapubs/4483
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
Included in
Bacterial Infections and Mycoses Commons, Medicinal-Pharmaceutical Chemistry Commons, Microbiology Commons, Pharmacy and Pharmaceutical Sciences Commons