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

TitlePlasticity of the Mycobacterium tuberculosis respiratory chain and its impact on tuberculosis drug development.
Publication TypeJournal Article
Year of Publication2019
AuthorsBeites T, O'Brien K, Tiwari D, Engelhart CA, Walters S, Andrews J, Yang H-J, 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
JournalNat Commun
Date Published2019 10 31
KeywordsAdaptation, Physiological, Animals, Antitubercular Agents, Callithrix, Drug Development, Electron Transport, Electron Transport Complex III, Electron Transport Complex IV, Gene Knockdown Techniques, Imidazoles, In Vitro Techniques, Lung, Mice, Mycobacterium tuberculosis, NADH Dehydrogenase, Piperidines, Pyridines, Tuberculosis, Tuberculosis, Pulmonary

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.

Alternate JournalNat Commun
PubMed ID31672993
PubMed Central IDPMC6823465
Grant ListS10 OD023524 / OD / NIH HHS / United States
U19 AI111143 / AI / NIAID NIH HHS / United States
OPP1154895 / / Bill and Melinda Gates Foundation (Bill & Melinda Gates Foundation) / International

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