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

October 31, 2019

Compounds were solubilized in DMSO and dispensed into 384-well plates using a D300e Digital Dispenser (HP)

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.

Beites, T; O'Brien, K; Tiwari, D; Engelhart, CA; Walters, S; Andrews, J; Yang, HJ; 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;

Journal: Nat Commun Pages: 4970

Original article (31672993)