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Proc Natl Acad Sci U S A. 2017 Jul 11;114(28):7426-7431. doi: 10.1073/pnas.1706139114. Epub 2017 Jun 26.

Exploiting the synthetic lethality between terminal respiratory oxidases to kill Mycobacterium tuberculosis and clear host infection.

Author information

1
Lee Kong Chian School of Medicine and School of Biological Sciences, Nanyang Technological University, Singapore 636921.
2
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461.
3
Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456.
4
Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore 117456.
5
Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, 9054 Dunedin, New Zealand.
6
School of Biological Sciences, Nanyang Technological University, Singapore 637551.
7
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461; kevin.pethe@ntu.edu.sg michael.berney@einstein.yu.edu.
8
Lee Kong Chian School of Medicine and School of Biological Sciences, Nanyang Technological University, Singapore 636921; kevin.pethe@ntu.edu.sg michael.berney@einstein.yu.edu.

Abstract

The recent discovery of small molecules targeting the cytochrome bc1 :aa3 in Mycobacterium tuberculosis triggered interest in the terminal respiratory oxidases for antituberculosis drug development. The mycobacterial cytochrome bc1 :aa3 consists of a menaquinone:cytochrome c reductase (bc1 ) and a cytochrome aa3 -type oxidase. The clinical-stage drug candidate Q203 interferes with the function of the subunit b of the menaquinone:cytochrome c reductase. Despite the affinity of Q203 for the bc1 :aa3 complex, the drug is only bacteriostatic and does not kill drug-tolerant persisters. This raises the possibility that the alternate terminal bd-type oxidase (cytochrome bd oxidase) is capable of maintaining a membrane potential and menaquinol oxidation in the presence of Q203. Here, we show that the electron flow through the cytochrome bd oxidase is sufficient to maintain respiration and ATP synthesis at a level high enough to protect M. tuberculosis from Q203-induced bacterial death. Upon genetic deletion of the cytochrome bd oxidase-encoding genes cydAB, Q203 inhibited mycobacterial respiration completely, became bactericidal, killed drug-tolerant mycobacterial persisters, and rapidly cleared M. tuberculosis infection in vivo. These results indicate a synthetic lethal interaction between the two terminal respiratory oxidases that can be exploited for anti-TB drug development. Our findings should be considered in the clinical development of drugs targeting the cytochrome bc1 :aa3 , as well as for the development of a drug combination targeting oxidative phosphorylation in M. tuberculosis.

KEYWORDS:

Q203; bedaquiline; bioenergetics; oxidative phosphorylation; persisters

PMID:
28652330
PMCID:
PMC5514758
DOI:
10.1073/pnas.1706139114
[Indexed for MEDLINE]
Free PMC Article

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