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Cytochrome <jats:italic>bc1-aa3<\/jats:italic> oxidase and type-2 NADH dehydrogenase (NDH-2) are respiratory chain components predicted to be essential, and are\u00a0currently targeted for drug development. Here we demonstrate that an <jats:italic>Mtb<\/jats:italic> cytochrome <jats:italic>bc1-aa3<\/jats:italic> oxidase deletion mutant is viable and only partially attenuated in mice. Moreover, treatment of <jats:italic>Mtb<\/jats:italic>-infected marmosets with a cytochrome <jats:italic>bc1-aa3<\/jats:italic> oxidase inhibitor controls disease progression and reduces lesion-associated inflammation, but most lesions become cavitary. Deletion of both NDH-2 encoding genes (\u0394<jats:italic>ndh-2<\/jats:italic> mutant) reveals that the essentiality of NDH-2 as shown in standard growth media is due to the presence of fatty acids. The \u0394<jats:italic>ndh-2<\/jats:italic> 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 <jats:italic>Mtb<\/jats:italic>\u2019s respiratory chain, and highlight the challenges associated with targeting the pathogen\u2019s respiratory enzymes for tuberculosis drug development.<\/jats:p>","DOI":"10.1038\/s41467-019-12956-2","type":"journal-article","created":{"date-parts":[[2019,10,31]],"date-time":"2019-10-31T11:08:43Z","timestamp":1572520123000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":131,"title":["Plasticity of the Mycobacterium tuberculosis respiratory chain and its impact on tuberculosis drug development"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7366-2107","authenticated-orcid":false,"given":"Tiago","family":"Beites","sequence":"first","affiliation":[]},{"given":"Kathryn","family":"O\u2019Brien","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7631-2471","authenticated-orcid":false,"given":"Divya","family":"Tiwari","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9324-5861","authenticated-orcid":false,"given":"Curtis A.","family":"Engelhart","sequence":"additional","affiliation":[]},{"given":"Shaun","family":"Walters","sequence":"additional","affiliation":[]},{"given":"Jenna","family":"Andrews","sequence":"additional","affiliation":[]},{"given":"Hee-Jeong","family":"Yang","sequence":"additional","affiliation":[]},{"given":"Michelle L.","family":"Sutphen","sequence":"additional","affiliation":[]},{"given":"Danielle M.","family":"Weiner","sequence":"additional","affiliation":[]},{"given":"Emmanuel K.","family":"Dayao","sequence":"additional","affiliation":[]},{"given":"Matthew","family":"Zimmerman","sequence":"additional","affiliation":[]},{"given":"Brendan","family":"Prideaux","sequence":"additional","affiliation":[]},{"given":"Prashant V.","family":"Desai","sequence":"additional","affiliation":[]},{"given":"Thierry","family":"Masquelin","sequence":"additional","affiliation":[]},{"given":"Laura E.","family":"Via","sequence":"additional","affiliation":[]},{"given":"V\u00e9ronique","family":"Dartois","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4333-206X","authenticated-orcid":false,"given":"Helena I.","family":"Boshoff","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2927-270X","authenticated-orcid":false,"suffix":"III","given":"Clifton E.","family":"Barry","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7951-2310","authenticated-orcid":false,"given":"Sabine","family":"Ehrt","sequence":"additional","affiliation":[]},{"given":"Dirk","family":"Schnappinger","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2019,10,31]]},"reference":[{"key":"12956_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.4103\/2229-516X.112228","volume":"3","author":"R Mahajan","year":"2013","unstructured":"Mahajan, R. 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