Two-way regulation of MmpL3 expression identifies and validates inhibitors of MmpL3 function in Mycobacterium tuberculosis Journal Article
| Authors: | Grover, S.; Engelhart, C. A.; Pérez-Herrán, E.; Li, W.; Abrahams, K. A.; Papavinasasundaram, K.; Bean, J. M.; Sassetti, C. M.; Mendoza-Losana, A.; Besra, G. S.; Jackson, M.; Schnappinger, D. |
| Article Title: | Two-way regulation of MmpL3 expression identifies and validates inhibitors of MmpL3 function in Mycobacterium tuberculosis |
| 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. © 2020 American Chemical Society. |
| Keywords: | protein expression; carrier protein; unclassified drug; nonhuman; molecular genetics; phenotype; drug discovery; validation study; bacterial protein; mycobacterium tuberculosis; mycolic acids; regulatory mechanism; respiration; bacterial growth; antibiotics; guanidine; cytochrome; whole cell; priority journal; article; targeted whole-cell screen; protein mmpl 3 |
| Journal Title: | ACS Infectious Diseases |
| Volume: | 7 |
| Issue: | 1 |
| ISSN: | 2373-8227 |
| Publisher: | American Chemical Society |
| Date Published: | 2021-01-08 |
| Start Page: | 141 |
| End Page: | 152 |
| Language: | English |
| DOI: | 10.1021/acsinfecdis.0c00675 |
| PUBMED: | 33319550 |
| PROVIDER: | scopus |
| PMCID: | PMC7802072 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 March 2021 -- Source: Scopus |
