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

doi:10.1038/s41467-019-12956-2

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 journal › Article › peer-review

14 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 language	English (US)
Article number	4970
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-12956-2
State	Published - Dec 1 2019
Externally published	Yes

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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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), Article 4970. https://doi.org/10.1038/s41467-019-12956-2

Beites, T, O’Brien, K, Tiwari, D, Engelhart, CA, Walters, S, Andrews, J, Yang, HJ, Sutphen, ML, Weiner, DM, Dayao, EK, Zimmerman, M, Prideaux, B, Desai, PV, Masquelin, T, Via, LE, Dartois, V, Boshoff, HI, Barry, CE, Ehrt, S & Schnappinger, D 2019, 'Plasticity of the Mycobacterium tuberculosis respiratory chain and its impact on tuberculosis drug development', Nature communications, vol. 10, no. 1, 4970. https://doi.org/10.1038/s41467-019-12956-2

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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{\textquoteright}s respiratory chain, and highlight the challenges associated with targeting the pathogen{\textquoteright}s respiratory enzymes for tuberculosis drug development.",

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AU - Dayao, Emmanuel K.

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AU - Prideaux, Brendan

AU - Desai, Prashant V.

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AU - Ehrt, Sabine

AU - Schnappinger, Dirk

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N2 - 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.

AB - 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.

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

Abstract

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