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

Nature communications, Volume: 10, Issue: 1
October 31, 2019
Tiago Beites T, Kathryn O'Brien K, Divya Tiwari D, Curtis A Engelhart CA, Shaun Walters S, Jenna Andrews J, Hee-Jeong Yang HJ, Michelle L Sutphen ML, Danielle M Weiner DM, Emmanuel K Dayao EK, Matthew Zimmerman M, Brendan Prideaux B, Prashant V Desai PV, Thierry Masquelin T, Laura E Via LE, Véronique Dartois V, Helena I Boshoff HI, Clifton E Barry CE, Sabine Ehrt S, Dirk Schnappinger D

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.