Plasticity of the Mycobacterium tuberculosis respiratory chain and its impact on tuberculosis drug development.
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10
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10.1038/s41467-019-12956-2
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Nature Communications
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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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Beites, T; O'Brien, K; Tiwari, D; Engelhart, CA; Walters, S; Andrews, J; Yang, H-J; Sutphen, ML; Weiner, DM; Dayao, EKCollections
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Except where otherwise noted, this item's license is described as Creative Commons Attribution 4.0 International License
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