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https://doi.org/10.15252/emmm.202013207
Title: | Dual inhibition of the terminal oxidases eradicates antibiotic-tolerant Mycobacterium tuberculosis | Authors: | Lee, Bei Shi Hards, Kiel Engelhart, Curtis A. Hasenoehrl, Erik J. Kalia, Nitin P. Mackenzie, Jared S. Sviriaeva, Ekaterina Chong, Shi Min Sherilyn Manimekalai, Malathy Sony S. Koh, Vanessa H. Chan, John Xu, Jiayong Alonso, Sylvie Miller, Marvin J. Steyn, Adrie J. C. Grüber, G. Schnappinger, Dirk Berney, Michael Cook, Gregory M. Moraski, Garrett C. Pethe, Kevin |
Keywords: | antibiotic-tolerance cytochrome bcc-aa3 cytochrome bd oxidase oxidative phosphorylation Q203 |
Issue Date: | 7-Dec-2020 | Publisher: | Blackwell Publishing Ltd | Citation: | Lee, Bei Shi, Hards, Kiel, Engelhart, Curtis A., Hasenoehrl, Erik J., Kalia, Nitin P., Mackenzie, Jared S., Sviriaeva, Ekaterina, Chong, Shi Min Sherilyn, Manimekalai, Malathy Sony S., Koh, Vanessa H., Chan, John, Xu, Jiayong, Alonso, Sylvie, Miller, Marvin J., Steyn, Adrie J. C., Grüber, G., Schnappinger, Dirk, Berney, Michael, Cook, Gregory M., Moraski, Garrett C., Pethe, Kevin (2020-12-07). Dual inhibition of the terminal oxidases eradicates antibiotic-tolerant Mycobacterium tuberculosis. EMBO Molecular Medicine 13 (1) : e13207. ScholarBank@NUS Repository. https://doi.org/10.15252/emmm.202013207 | Rights: | Attribution 4.0 International | Abstract: | The approval of bedaquiline has placed energy metabolism in the limelight as an attractive target space for tuberculosis antibiotic development. While bedaquiline inhibits the mycobacterial F1F0 ATP synthase, small molecules targeting other components of the oxidative phosphorylation pathway have been identified. Of particular interest is Telacebec (Q203), a phase 2 drug candidate inhibitor of the cytochrome bcc:aa3 terminal oxidase. A functional redundancy between the cytochrome bcc:aa3 and the cytochrome bd oxidase protects M. tuberculosis from Q203-induced death, highlighting the attractiveness of the bd-type terminal oxidase for drug development. Here, we employed a facile whole-cell screen approach to identify the cytochrome bd inhibitor ND-011992. Although ND-011992 is ineffective on its own, it inhibits respiration and ATP homeostasis in combination with Q203. The drug combination was bactericidal against replicating and antibiotic-tolerant, non-replicating mycobacteria, and increased efficacy relative to that of a single drug in a mouse model. These findings suggest that a cytochrome bd oxidase inhibitor will add value to a drug combination targeting oxidative phosphorylation for tuberculosis treatment. © 2020 The Authors. Published under the terms of the CC BY 4.0 license | Source Title: | EMBO Molecular Medicine | URI: | https://scholarbank.nus.edu.sg/handle/10635/233278 | ISSN: | 1757-4676 | DOI: | 10.15252/emmm.202013207 | Rights: | Attribution 4.0 International |
Appears in Collections: | Elements Staff Publications |
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