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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 Pal
Mackenzie, Jared S.
Sviriaeva, Ekaterina
Chong, Sherilyn Shi Min
Manimekalai, Malathy Sony S.
Koh, Vanessa H.
Chan, John
Xu, Jiayong
Alonso, Sylvie
Miller, Marvin J.
Steyn, Adrie J. C.
Grüber, Gerhard
Schnappinger, Dirk
Berney, Michael
Cook, Gregory M.
Moraski, Garrett C.
Pethe, Kevin
Keywords: Science::Chemistry::Biochemistry
Issue Date: 2021
Source: Lee, B. S., Hards, K., Engelhart, C. A., Hasenoehrl, E. J., Kalia, N. P., Mackenzie, J. S., Sviriaeva, E., Chong, S. S. M., Manimekalai, M. S. S., Koh, V. H., Chan, J., Xu, J., Alonso, S., Miller, M. J., Steyn, A. J. C., Grüber, G., Schnappinger, D., Berney, M., Cook, G. M., ...Pethe, K. (2021). Dual inhibition of the terminal oxidases eradicates antibiotic-tolerant Mycobacterium tuberculosis. EMBO Molecular Medicine, 13(1).
Project: NRF-CRP18-2017-01
Journal: EMBO Molecular Medicine
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.
ISSN: 1757-4676 (print) 1757-4684 (web)
DOI: 10.15252/emmm.202013207
Rights: © 2020 The Authors. This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:SBS Journal Articles

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