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

Author

Listed:
  • Tiago Beites

    (Weill Cornell Medical College)

  • Kathryn O’Brien

    (Weill Cornell Medical College)

  • Divya Tiwari

    (Weill Cornell Medical College)

  • Curtis A. Engelhart

    (Weill Cornell Medical College)

  • Shaun Walters

    (Weill Cornell Medical College
    University of Queensland)

  • Jenna Andrews

    (Laboratory of Clinical Immunology and Microbiology, NIAID, NIH)

  • Hee-Jeong Yang

    (Laboratory of Clinical Immunology and Microbiology, NIAID, NIH)

  • Michelle L. Sutphen

    (Laboratory of Clinical Immunology and Microbiology, NIAID, NIH)

  • Danielle M. Weiner

    (Laboratory of Clinical Immunology and Microbiology, NIAID, NIH)

  • Emmanuel K. Dayao

    (Laboratory of Clinical Immunology and Microbiology, NIAID, NIH)

  • Matthew Zimmerman

    (Hackensack Meridian Health)

  • Brendan Prideaux

    (Hackensack Meridian Health)

  • Prashant V. Desai

    (Eli Lilly and Company)

  • Thierry Masquelin

    (Eli Lilly and Company)

  • Laura E. Via

    (Laboratory of Clinical Immunology and Microbiology, NIAID, NIH
    University of Cape Town)

  • Véronique Dartois

    (Hackensack Meridian Health)

  • Helena I. Boshoff

    (Laboratory of Clinical Immunology and Microbiology, NIAID, NIH)

  • Clifton E. Barry

    (Laboratory of Clinical Immunology and Microbiology, NIAID, NIH
    University of Cape Town)

  • Sabine Ehrt

    (Weill Cornell Medical College)

  • Dirk Schnappinger

    (Weill Cornell Medical College)

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.

Suggested Citation

  • 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 , 2019. "Plasticity of the Mycobacterium tuberculosis respiratory chain and its impact on tuberculosis drug development," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12956-2
    DOI: 10.1038/s41467-019-12956-2
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    Cited by:

    1. Natalie J. E. Waller & Chen-Yi Cheung & Gregory M. Cook & Matthew B. McNeil, 2023. "The evolution of antibiotic resistance is associated with collateral drug phenotypes in Mycobacterium tuberculosis," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Tiago Beites & Robert S. Jansen & Ruojun Wang & Adrian Jinich & Kyu Y. Rhee & Dirk Schnappinger & Sabine Ehrt, 2021. "Multiple acyl-CoA dehydrogenase deficiency kills Mycobacterium tuberculosis in vitro and during infection," Nature Communications, Nature, vol. 12(1), pages 1-10, December.

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