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The diarylquinoline bedaquiline has recently emerged as a highly efficacious drug against MDR-TB and kills\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    by inhibiting mycobacterial\u00a0ATP synthase. However, the\u00a0mechanisms underlying bedaquiline\u2019s efficacy against MDR-TB remain unknown. Here we investigate bedaquiline hyper-susceptibility in drug-resistant\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    using systems biology approaches. We discovered that MDR clinical isolates are commonly sensitized to bedaquiline. This hypersensitization is caused by several physiological changes induced by deficient catalase activity. These include enhanced accumulation of reactive oxygen species, increased susceptibility to DNA damage, induction of sensitizing transcriptional programs, and metabolic repression of several biosynthetic pathways. In this work we demonstrate how resistance-associated changes in bacterial physiology can mechanistically\u00a0induce collateral antimicrobial drug sensitivity and reveal druggable vulnerabilities in antimicrobial resistant pathogens.\n                  <\/jats:p>","DOI":"10.1038\/s41467-024-53933-8","type":"journal-article","created":{"date-parts":[[2024,11,13]],"date-time":"2024-11-13T05:54:17Z","timestamp":1731477257000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Catalase activity deficiency sensitizes multidrug-resistant Mycobacterium tuberculosis to the ATP synthase inhibitor bedaquiline"],"prefix":"10.1038","volume":"15","author":[{"given":"Boatema","family":"Ofori-Anyinam","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meagan","family":"Hamblin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miranda L.","family":"Coldren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1102-561X","authenticated-orcid":false,"given":"Barry","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gautam","family":"Mereddy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mustafa","family":"Shaikh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avi","family":"Shah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney","family":"Grady","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Navpreet","family":"Ranu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4889-8783","authenticated-orcid":false,"given":"Paul C.","family":"Blainey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0783-1328","authenticated-orcid":false,"given":"Shuyi","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5560-8246","authenticated-orcid":false,"given":"James J.","family":"Collins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0921-4657","authenticated-orcid":false,"given":"Jason H.","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,11,13]]},"reference":[{"key":"53933_CR1","unstructured":"World Health, Organization. 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