Title | Dual inhibition of the terminal oxidases eradicates antibiotic-tolerant Mycobacterium tuberculosis. |
Publication Type | Journal Article |
Year of Publication | 2021 |
Authors | Lee 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 |
Journal | EMBO Mol Med |
Volume | 13 |
Issue | 1 |
Pagination | e13207 |
Date Published | 2021 Jan 11 |
ISSN | 1757-4684 |
Keywords | Animals, 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. |
DOI | 10.15252/emmm.202013207 |
Alternate Journal | EMBO Mol Med |
PubMed ID | 33283973 |
PubMed Central ID | PMC7799364 |
Grant List | R01 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 |
Submitted by ljc4002 on August 21, 2025 - 2:26pm