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 and Dirk Schnappinger ()
Additional contact information
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
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
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
Sabine Ehrt: Weill Cornell Medical College
Dirk Schnappinger: Weill Cornell Medical College

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12956-2

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