Plasticity of the Mycobacterium tuberculosis respiratory chain and its impact on tuberculosis drug development

Tiago Beites, Kathryn O’Brien, Divya Tiwari, Curtis A. Engelhart, Shaun Walters, Jenna Andrews, Hee Jeong Yang, Michelle L. Sutphen, Danielle M. Weiner, Emmanuel K. Dayao, Matthew Zimmerman, Brendan Prideaux, Prashant V. Desai, Thierry Masquelin, Laura E. Via, Véronique Dartois, Helena I. Boshoff, Clifton E. Barry, Sabine Ehrt, Dirk Schnappinger

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

The viability of Mycobacterium tuberculosis (Mtb) depends on energy generated by its respiratory chain. Cytochrome bc1-aa3 oxidase and type-2 NADH dehydrogenase (NDH-2) are respiratory chain components predicted to be essential, and are currently targeted for drug development. Here we demonstrate that an Mtb cytochrome bc1-aa3 oxidase deletion mutant is viable and only partially attenuated in mice. Moreover, treatment of Mtb-infected marmosets with a cytochrome bc1-aa3 oxidase inhibitor controls disease progression and reduces lesion-associated inflammation, but most lesions become cavitary. Deletion of both NDH-2 encoding genes (Δndh-2 mutant) reveals that the essentiality of NDH-2 as shown in standard growth media is due to the presence of fatty acids. The Δndh-2 mutant is only mildly attenuated in mice and not differently susceptible to clofazimine, a drug in clinical use proposed to engage NDH-2. These results demonstrate the intrinsic plasticity of Mtb’s respiratory chain, and highlight the challenges associated with targeting the pathogen’s respiratory enzymes for tuberculosis drug development.

Original languageEnglish (US)
Article number4970
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Fingerprint Dive into the research topics of 'Plasticity of the Mycobacterium tuberculosis respiratory chain and its impact on tuberculosis drug development'. Together they form a unique fingerprint.

  • Cite this

    Beites, T., O’Brien, K., Tiwari, D., Engelhart, C. A., Walters, S., Andrews, J., Yang, H. J., Sutphen, M. L., Weiner, D. M., Dayao, E. K., Zimmerman, M., Prideaux, B., Desai, P. V., Masquelin, T., Via, L. E., Dartois, V., Boshoff, H. I., Barry, C. E., Ehrt, S., & Schnappinger, D. (2019). Plasticity of the Mycobacterium tuberculosis respiratory chain and its impact on tuberculosis drug development. Nature communications, 10(1), [4970]. https://doi.org/10.1038/s41467-019-12956-2