{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T05:47:16Z","timestamp":1782798436065,"version":"3.54.5"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Tuberc."],"abstract":"<jats:p>\n                    Mycobacterial drug resistance leads to prolonged treatment, increased mortality, and increased healthcare costs. In this study, 3-azidothiophene-2-carboxylic acid (ACA), a dual-targeting inhibitor of the cell assembly proteins CpsA1 and CpsA2, exerted its activity through an iron-dependent pathway. The screening of drug-resistant mutants revealed that a frameshift mutation in the transcriptional regulator\n                    <jats:italic>acasR<\/jats:italic>\n                    (BCG_0932\/Rv0880) conferred ACA resistance. Conversely,\n                    <jats:italic>acasR<\/jats:italic>\n                    overexpression increased bacterial susceptibility. Furthermore, AcasR specifically bound to and repressed the promoter of\n                    <jats:italic>fadD9<\/jats:italic>\n                    (Rv2590), which was its sole functionally validated target under the tested conditions. Crucially,\n                    <jats:italic>fadD9<\/jats:italic>\n                    overexpression phenocopied ACA resistance, whereas its deletion heightened susceptibility. Integrated omics and iron assays revealed that ACA induced intracellular iron starvation, a condition exacerbated by\n                    <jats:italic>fadD9<\/jats:italic>\n                    deletion. These findings reveal a novel resistance pathway in which AcasR modulates mycobacterial drug susceptibility by repressing\n                    <jats:italic>fadD9<\/jats:italic>\n                    , which in turn affects siderophore-mediated iron homeostasis.\n                  <\/jats:p>","DOI":"10.3389\/ftubr.2026.1830528","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T05:42:00Z","timestamp":1782798120000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The AcasR-FadD9 regulatory axis modulates iron homeostasis and susceptibility to the anti-mycobacterial compound ACA"],"prefix":"10.3389","volume":"4","author":[{"given":"Feng","family":"Huang","sequence":"first","affiliation":[{"name":"National Key Laboratory of Agricultural Microbiology, College of Life Science and Technology, Huazhong Agricultural University","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zixin","family":"Wang","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Agricultural Microbiology, College of Life Science and Technology, Huazhong Agricultural University","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Jiang","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Agricultural Microbiology, College of Life Science and Technology, Huazhong Agricultural University","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengyi","family":"Li","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Agricultural Microbiology, College of Life Science and Technology, Huazhong Agricultural University","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng-Guo","family":"He","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Virology, Taikang Center for Life and Medical Sciences, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University","place":["Wuhan, China"]},{"name":"College of Life Science and Technology, Guangxi University","place":["Nanning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Zhang","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Agricultural Microbiology, College of Life Science and Technology, Huazhong Agricultural University","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"956602","DOI":"10.3389\/fmicb.2022.956602","article-title":"Iron deprivation enhances transcriptional responses to in vitro growth arrest of Mycobacterium tuberculosis","volume":"13","author":"Alebouyeh","year":"2022","journal-title":"Front Microbiol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"e102135","DOI":"10.1371\/journal.pone.0102135","article-title":"Acquired resistance of Mycobacterium tuberculosis to bedaquiline","volume":"9","author":"Andries","year":"2014","journal-title":"PLoS One"},{"key":"B3","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1038\/nchembio.143","article-title":"Mechanistic and functional insights into fatty acid activation in","volume":"5","author":"Arora","year":"2009","journal-title":"Mycobacterium tuberculosis. 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