Please use this identifier to cite or link to this item: 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
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