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The most common mutation is a single amino acid substitution, \u03b2S450L, that confers antibiotic resistance. This mutation also results in collateral effects that impact bacterial physiology and fitness, although the mechanisms underlying many of these effects remain unclear. Here we employed a CRISPRi comparative functional genomics approach to analyse gene vulnerability differences between \u03b2S450L Mtb and two alternative Rif-resistant (RifR) Mtb strains, \u03b2D435V and \u03b2H445Y. Among the strongest \u03b2S450L-specific vulnerabilities, we identified thiamine and branched-chain amino acid (BCAA) biosynthesis pathways. These vulnerabilities arise, at least in part, due to transcription attenuation, which impairs \u03b2S450L Mtb\u2019s ability to upregulate expression of the critical BCAA biosynthetic enzyme\n                    <jats:italic>ilvB1<\/jats:italic>\n                    in response to genetic or chemical inhibition. Together, our findings highlight the distinct physiological impacts of RifR in Mtb, identify transcription attenuation as a key driver of \u03b2S450L-specific vulnerabilities, and suggest potential avenues for targeted intervention.\n                  <\/jats:p>","DOI":"10.1038\/s41564-026-02357-9","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T09:03:43Z","timestamp":1779181423000},"page":"1696-1710","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Transcription attenuation amplifies collateral vulnerabilities in rifampicin-resistant Mycobacterium tuberculosis"],"prefix":"10.1038","volume":"11","author":[{"given":"Kathryn A.","family":"Eckartt","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0925-9632","authenticated-orcid":false,"given":"Vanisha","family":"Munsamy-Govender","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefany","family":"Qui\u00f1ones-Garcia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3867-0299","authenticated-orcid":false,"given":"Michael A.","family":"DeJesus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7831-0899","authenticated-orcid":false,"given":"Xiangwu","family":"Ju","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4238-7066","authenticated-orcid":false,"given":"Shixin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9310-951X","authenticated-orcid":false,"given":"Jeremy M.","family":"Rock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,19]]},"reference":[{"key":"2357_CR1","unstructured":"Global Tuberculosis Report 2024 (WHO, 2024)."},{"key":"2357_CR2","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1038\/nrmicro2319","volume":"8","author":"DI Andersson","year":"2010","unstructured":"Andersson, D. 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