{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T07:01:22Z","timestamp":1780038082801,"version":"3.53.1"},"reference-count":63,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T00:00:00Z","timestamp":1780012800000},"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. Microbiol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Xenobiotic response element (XRE) family transcriptional regulators play crucial roles in diverse bacterial physiological processes and environmental adaptation. However, the functional characterization of these regulators in\n                      <jats:italic>Clostridioides difficile<\/jats:italic>\n                      remains unclear.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      In this study, we employed the Allele-coupled exchange (ACE) gene knockout technique to construct knockout (\u0394\n                      <jats:italic>xtr<\/jats:italic>\n                      ) and complemented (::\n                      <jats:italic>xtr<\/jats:italic>\n                      ) mutants of the\n                      <jats:italic>xtr<\/jats:italic>\n                      gene, which encodes a member of the XRE family protein in\n                      <jats:italic>C. difficile<\/jats:italic>\n                      , and systematically analyzed the resulting phenotypic alterations. Subsequently, transcriptome sequencing, EMSA, and reporter gene assays were utilized to investigate how\n                      <jats:italic>xtr<\/jats:italic>\n                      regulates 4Fe-4S binding protein gene (\n                      <jats:italic>4Fe-4S_BP<\/jats:italic>\n                      ,\n                      <jats:italic>CD17960<\/jats:italic>\n                      ).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The \u0394\n                      <jats:italic>xtr<\/jats:italic>\n                      mutant exhibited a statistically significant reduction in hydrogen peroxide tolerance, as well as decreased susceptibility to vancomycin and metronidazole. Concomitantly, the expression of virulence-related genes and cellular toxicity, as well as growth rate and autolysis, were all notably diminished. Transcriptomic analysis revealed a significant downregulation of\n                      <jats:italic>4Fe-4S_BP<\/jats:italic>\n                      in the \u0394\n                      <jats:italic>xtr<\/jats:italic>\n                      mutant (3.69-fold). Overexpression of the\n                      <jats:italic>4Fe-4S_BP<\/jats:italic>\n                      in the \u0394\n                      <jats:italic>xtr<\/jats:italic>\n                      background restored hydrogen peroxide tolerance to wild-type levels. Electrophoretic Mobility Shift Assays (EMSA) confirmed that the recombinant Xtr protein directly binds to the promoter region of\n                      <jats:italic>4Fe-4S_BP<\/jats:italic>\n                      . Reporter gene assays utilizing\n                      <jats:italic>gusA<\/jats:italic>\n                      demonstrated that Xtr activates transcription from the\n                      <jats:italic>4Fe-4S_BP<\/jats:italic>\n                      promoters.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      These findings elucidate a molecular mechanism by which Xtr positively regulates the expression of\n                      <jats:italic>4Fe-4S_BP<\/jats:italic>\n                      , thereby modulating\n                      <jats:italic>C. difficile<\/jats:italic>\n                      tolerance to hydrogen peroxide, metronidazole, and vancomycin. This work provides novel experimental evidence for a deeper understanding of the environmental adaptation strategies and virulence regulatory networks employed by\n                      <jats:italic>C. difficile<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmicb.2026.1817884","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T06:01:42Z","timestamp":1780034502000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Xtr-mediated regulation of 4Fe-4S binding protein gene confers resistance to oxidative and antibiotic stress in Clostridioides difficile"],"prefix":"10.3389","volume":"17","author":[{"given":"Wenjing","family":"Wu","sequence":"first","affiliation":[{"name":"Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education, Guizhou Medical University, Guiyang","place":["Guizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Zhou","sequence":"additional","affiliation":[{"name":"Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education, Guizhou Medical University, Guiyang","place":["Guizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fahui","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education, Guizhou Medical University, Guiyang","place":["Guizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education, Guizhou Medical University, Guiyang","place":["Guizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Xie","sequence":"additional","affiliation":[{"name":"Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education, Guizhou Medical University, Guiyang","place":["Guizhou, China"]},{"name":"Collaborative Innovation Center for Prevention and Control of Endemic and Ethnic Regional Diseases Co-constructed by the Province and Ministry, Guiyang","place":["Guizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guzhen","family":"Cui","sequence":"additional","affiliation":[{"name":"Key Laboratory of Microbiology and Parasitology of the Education Department of Guizhou, Guizhou Medical University","place":["Guiyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhizhong","family":"Guan","sequence":"additional","affiliation":[{"name":"Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education, Guizhou Medical University, Guiyang","place":["Guizhou, China"]},{"name":"Collaborative Innovation Center for Prevention and Control of Endemic and Ethnic Regional Diseases Co-constructed by the Province and Ministry, Guiyang","place":["Guizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education, Guizhou Medical University, Guiyang","place":["Guizhou, China"]},{"name":"Collaborative Innovation Center for Prevention and Control of Endemic and Ethnic Regional Diseases Co-constructed by the Province and Ministry, Guiyang","place":["Guizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Hong","sequence":"additional","affiliation":[{"name":"Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education, Guizhou Medical University, Guiyang","place":["Guizhou, China"]},{"name":"Collaborative Innovation Center for Prevention and Control of Endemic and Ethnic Regional Diseases Co-constructed by the Province and Ministry, Guiyang","place":["Guizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"102062","DOI":"10.1016\/j.redox.2021.102062","article-title":"Mycobacterium tuberculosis SufR responds to nitric oxide via its 4Fe\u20134S cluster and regulates Fe\u2013S cluster biogenesis for persistence in mice.","volume":"46","author":"Anand","year":"2021","journal-title":"Redox Biol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1112","DOI":"10.1042\/BST0361112","article-title":"Iron\u2013sulfur cluster biosynthesis.","volume":"36","author":"Bandyopadhyay","year":"2008","journal-title":"Biochem. 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