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CodY is a global transcriptional regulator that coordinates metabolism and virulence in Gram\u2010positive pathogens by sensing branched\u2010chain amino acids and GTP. In\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>C. difficile<\/jats:italic>\n                    <\/jats:styled-content>\n                    , CodY represses toxin production by inhibiting transcription of\n                    <jats:italic>tcdR<\/jats:italic>\n                    and by influencing c\u2010di\u2010GMP turnover. Here, we characterized two naturally occurring CodY variants, CodY(Y146N) and CodY(V58A), whose substitutions lie near the GTP\u2010 and ILV\u2010binding sites, respectively. GTP\u2010binding by CodY(Y146N) was severely compromised, while leucine binding was enhanced; CodY(V58A) showed reduced leucine binding. Both variants exhibited reduced ligand\u2010dependent binding to the\n                    <jats:italic>tcdR<\/jats:italic>\n                    promoter and failed to repress toxin production as effectively as CodY(WT). Expression of virulence\u2010associated genes (\n                    <jats:italic>tcdR<\/jats:italic>\n                    ,\n                    <jats:italic>pdcB<\/jats:italic>\n                    ) was elevated in strains producing either variant. In a hamster infection model, both variant\u2010producing strains were significantly more virulent than the CodY(WT) strain. These findings demonstrate that single amino acid substitutions in this global regulator can alter ligand affinity and promoter binding, potentially rewiring gene regulatory networks to enhance the pathogenic potential of\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>C. difficile<\/jats:italic>\n                    <\/jats:styled-content>\n                    .\n                  <\/jats:p>","DOI":"10.1111\/mmi.70081","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T05:22:10Z","timestamp":1780464130000},"page":"98-110","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Naturally Occurring\n                    <scp>CodY<\/scp>\n                    Variants Alter Ligand Binding,\n                    <scp>DNA<\/scp>\n                    Target Affinity, and Virulence in\n                    <i>Clostridioides difficile<\/i>"],"prefix":"10.1111","volume":"126","author":[{"given":"Md Kamrul","family":"Hasan","sequence":"first","affiliation":[{"name":"Division of Biology Kansas State University  Manhattan Kansas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sourav","family":"Roy","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biophysics Kansas State University  Manhattan Kansas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Revathi","family":"Govind","sequence":"additional","affiliation":[{"name":"Division of Biology Kansas State University  Manhattan Kansas 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