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

Bei Shi Lee, Kiel Hards, Curtis A. Engelhart, Erik J. Hasenoehrl, Nitin P. Kalia, Jared S. Mackenzie, Ekaterina Sviriaeva, Shi Min Sherilyn Chong, Malathy Sony S. Manimekalai, Vanessa H. Koh, John Chan, Jiayong Xu, Sylvie Alonso, Marvin J. Miller, Adrie J.C. Steyn, Gerhard Grüber, Dirk Schnappinger, Michael Berney, Gregory M. Cook, Garrett C. MoraskiKevin Pethe

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

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.

Original languageEnglish (US)
Article numbere13207
JournalEMBO Molecular Medicine
Volume13
Issue number1
DOIs
StatePublished - Jan 11 2021

Keywords

  • Q203
  • antibiotic-tolerance
  • cytochrome bcc-aa3
  • cytochrome bd oxidase
  • oxidative phosphorylation

ASJC Scopus subject areas

  • Molecular Medicine

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