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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 (Δ ndh-2  mutant) reveals that the essentiality of NDH-2 as shown in standard growth media is due to the presence of fatty acids. The Δ ndh-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.

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