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.

Courtesy of the U.S. National Library of Medicine