Title | Plasticity of the Mycobacterium tuberculosis respiratory chain and its impact on tuberculosis drug development. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Beites T, O'Brien K, Tiwari D, Engelhart CA, Walters S, Andrews J, Yang H-J, 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 |
Volume | 10 |
Issue | 1 |
Pagination | 4970 |
Date Published | 2019 10 31 |
ISSN | 2041-1723 |
Keywords | Adaptation, Physiological, Animals, Antitubercular Agents, Callithrix, Drug Development, Electron Transport, Electron Transport Complex III, Electron Transport Complex IV, Gene Knockdown Techniques, Imidazoles, In Vitro Techniques, Lung, Mice, Mycobacterium tuberculosis, NADH Dehydrogenase, Piperidines, Pyridines, Tuberculosis, Tuberculosis, Pulmonary |
Abstract | 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. |
DOI | 10.1038/s41467-019-12956-2 |
Alternate Journal | Nat Commun |
PubMed ID | 31672993 |
PubMed Central ID | PMC6823465 |
Grant List | S10 OD023524 / OD / NIH HHS / United States U19 AI111143 / AI / NIAID NIH HHS / United States OPP1154895 / / Bill and Melinda Gates Foundation (Bill & Melinda Gates Foundation) / International |
Submitted by wcm_microbiolog... on October 13, 2020 - 1:43pm