Dual inhibition of the terminal oxidases eradicates antibiotic-tolerant Mycobacterium tuberculosis.

TitleDual inhibition of the terminal oxidases eradicates antibiotic-tolerant Mycobacterium tuberculosis.
Publication TypeJournal Article
Year of Publication2021
AuthorsLee BShi, Hards K, Engelhart CA, Hasenoehrl EJ, Kalia NP, Mackenzie JS, Sviriaeva E, Chong SMin Sheril, Manimekalai MSony S, Koh VH, Chan J, Xu J, Alonso S, Miller MJ, Steyn AJC, Grüber G, Schnappinger D, Berney M, Cook GM, Moraski GC, Pethe K
JournalEMBO Mol Med
Volume13
Issue1
Paginatione13207
Date Published2021 Jan 11
ISSN1757-4684
KeywordsAnimals, Anti-Bacterial Agents, Antitubercular Agents, Electron Transport Complex IV, Mice, Mycobacterium tuberculosis, Oxidoreductases, Tuberculosis
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 F1 F0 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.

DOI10.15252/emmm.202013207
Alternate JournalEMBO Mol Med
PubMed ID33283973
PubMed Central IDPMC7799364
Grant ListR01 AI139465 / AI / NIAID NIH HHS / United States
R01 AI137043 / AI / NIAID NIH HHS / United States
F30 AI138483 / AI / NIAID NIH HHS / United States
R01 AI054193 / AI / NIAID NIH HHS / United States
R37 AI054193 / AI / NIAID NIH HHS / United States

Weill Cornell Medicine Microbiology and Immunology 1300 York Avenue, Box 62 New York, NY 10065 Phone: (212) 746-6505 Fax: (212) 746-8587