Journal Article

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

Tiwari, Divya, Weiner, Danielle M., Zimmerman, Matthew, Schnappinger, Dirk, Desai, Prashant V., Engelhart, Curtis A., Prideaux, Brendan, Ehrt, Sabine, Dartois, Véronique, Boshoff, Helena I., O’Brien, Kathryn, Sutphen, Michelle L., Barry, Clifton E., Dayao, Emmanuel K., Beites, Tiago, Andrews, Jenna, Masquelin, Thierry, Via, Laura E., Walters, Shaun, Yang, Hee-Jeong

2019

Overview

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. New tuberculosis therapies, targeting respiratory chain components of Mycobacterium tuberculosis , are under development. Here the authors show that, contrary to common belief, some of these components are not essential for pathogen viability and/or virulence in animal models of infection.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38/70 / 38/77 / 38/88 / 38/90 / 631/154/556 / 631/326/325/2482 / 631/326/41/1969/2038 / 631/326/421 / 64/60 / Adaptation, Physiological - genetics / Animals / Antitubercular Agents - therapeutic use / Callithrix / Clofazimine / Cytochrome / Cytochrome bc1 / Cytochromes / Deletion mutant / Disease control / Drug Development / Electron Transport / Electron Transport Complex III - antagonists & inhibitors / Electron Transport Complex III - genetics / Electron Transport Complex IV - antagonists & inhibitors / Electron Transport Complex IV - genetics / Fatty acids / Gene Knockdown Techniques / Growth media / Humanities and Social Sciences / Imidazoles - pharmacology / In Vitro Techniques / Lesions / Lung - drug effects / Lung - pathology / Mice / multidisciplinary / Mycobacterium tuberculosis / Mycobacterium tuberculosis - drug effects / Mycobacterium tuberculosis - genetics / Mycobacterium tuberculosis - metabolism / NADH / NADH dehydrogenase / NADH Dehydrogenase - antagonists & inhibitors / NADH Dehydrogenase - genetics / Nicotinamide adenine dinucleotide / Oxidase / Piperidines - pharmacology / Plastic properties / Plasticity / Pyridines - pharmacology / Respiratory enzymes / Science / Science (multidisciplinary) / Tuberculosis / Tuberculosis - drug therapy / Tuberculosis, Pulmonary - drug therapy / Tuberculosis, Pulmonary - pathology / Viability