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In addition to target or activator mutations conferring canonical drug resistance, mutations can serve as steppingstones to or enhancers of resistance. In clinical strains of\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    (Mtb), we find that\n                    <jats:italic>idsA2,<\/jats:italic>\n                    which encodes an isoprenyl pyrophosphate synthase involved in the synthesis of precursors for essential components of the cell wall and electron transport chain, is undergoing diversifying selection in Lineage 4, and that these mutations are associated with the acquisition of first-line antibiotic resistance. By engineering isogenic Mtb strains to express clinically prevalent variants of\n                    <jats:italic>idsA2<\/jats:italic>\n                    , we show that\n                    <jats:italic>idsA2<\/jats:italic>\n                    variants alter the inhibitory concentrations of first-line drugs, most significantly increasing the inhibitory concentration of ethambutol by two-fold. Targeted lipid analyses reveal that disrupting IdsA2 function redirects limited resources in the isoprenoid synthesis pathway, leading to increased production of decaprenyl phosphate species. This suggests that\n                    <jats:italic>idsA2<\/jats:italic>\n                    and\n                    <jats:italic>ubiA<\/jats:italic>\n                    mutations share an ethambutol resistance mechanism. Where\n                    <jats:italic>idsA2<\/jats:italic>\n                    mutations arise after\n                    <jats:italic>embB<\/jats:italic>\n                    mutations, they maintain their multiplicative effect on the inhibitory concentration of ethambutol such that the variants together result in high-level resistance. As a result, identification of\n                    <jats:italic>idsA2<\/jats:italic>\n                    mutations can be utilized to improve the specificity of genotypic ethambutol susceptibility testing. Together, this work shows how\n                    <jats:italic>idsA2<\/jats:italic>\n                    mutations remodel bacterial metabolism and augment ethambutol resistance.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1014237","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T17:56:11Z","timestamp":1786730171000},"page":"e1014237","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Encoded metabolic remodeling amplifies drug resistance in Mycobacterium tuberculosis"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2688-1259","authenticated-orcid":true,"given":"Abigail M","family":"Frey","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory H.","family":"Babunovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter H.","family":"Culviner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ella","family":"Meirav","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyu","family":"Gan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junhao","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. Branch","family":"Moody","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingyun","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7565-9975","authenticated-orcid":true,"given":"Sarah M.","family":"Fortune","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,8,14]]},"reference":[{"issue":"9","key":"ppat.1014237.ref001","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1038\/s41579-025-01159-w","article-title":"Ecology, global diversity and evolutionary mechanisms in the Mycobacterium tuberculosis complex","volume":"23","author":"GA Goig","year":"2025","journal-title":"Nat Rev 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