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

Link to Article in PubMed

PubMed ID

33319550

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

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