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Current frontline therapies, including vancomycin and fidaxomicin, are associated with disruption of the intestinal microbiota, recurrence, and emerging reduced susceptibility, underscoring the need for additional therapeutic strategies. Using a drug-repurposing approach, we identified the antifungal agent abafungin as a potent inhibitor of\n                      <jats:italic toggle=\"yes\">C. difficile<\/jats:italic>\n                      . Abafungin is an arylguanidine antifungal with reported sporicidal activity against fungal pathogens, a property of particular relevance to CDI, given the central role of spores in disease persistence and recurrence. Herein, abafungin exhibited potent\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      activity against a diverse panel of clinical\n                      <jats:italic toggle=\"yes\">C. difficile<\/jats:italic>\n                      isolates, inhibiting 50% (MIC\n                      <jats:sub>5\u2080<\/jats:sub>\n                      ) and 90% (MIC\n                      <jats:sub>\u2089\u2080<\/jats:sub>\n                      ) of the tested strains at the concentrations of 0.25 \u03bcg\/mL and 0.5 \u03bcg\/mL, respectively, while demonstrating minimal activity against representative gut commensal bacteria. At sub-inhibitory concentrations, abafungin significantly reduced toxin production (31.8%), decreased spore formation (~4-log\u2081\u2080 reduction), and inhibited spore germination. Abafungin showed favorable gastrointestinal stability and demonstrated synergistic activity with vancomycin and metronidazole. Transcriptomic analysis revealed that abafungin disrupts metal ion transport and intracellular metal homeostasis in\n                      <jats:italic toggle=\"yes\">C. difficile<\/jats:italic>\n                      , a mechanism supported by the antagonistic effect of Mg\u00b2\n                      <jats:sup>+<\/jats:sup>\n                      supplementation on its antibacterial activity. These observations suggest a potential association between abafungin activity and metal-responsive cellular pathways. In a murine model of recurrent CDI, a combination therapy of abafungin and vancomycin significantly improved survival (83.3%) compared with vancomycin monotherapy (16.6%). Collectively, these findings establish abafungin as a potential anti\n                      <jats:italic toggle=\"yes\">-C<\/jats:italic>\n                      .\n                      <jats:italic toggle=\"yes\">difficile<\/jats:italic>\n                      inhibitor that suppresses\n                      <jats:italic toggle=\"yes\">C. difficile<\/jats:italic>\n                      growth and virulence-associated processes and enhances the therapeutic efficacy of vancomycin\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      . Also, these observations provide a basis for further studies exploring abafungin as a useful lead scaffold for anti\n                      <jats:italic toggle=\"yes\">-C<\/jats:italic>\n                      .\n                      <jats:italic toggle=\"yes\">difficile<\/jats:italic>\n                      drug discovery.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.00598-26","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T13:37:16Z","timestamp":1786628236000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Antibacterial and antivirulence activities of abafungin against\n                    <i>Clostridioides difficile<\/i>\n                    :\n                    <i>in vitro<\/i>\n                    and\n                    <i>in vivo<\/i>\n                    studies"],"prefix":"10.1128","volume":"70","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9937-742X","authenticated-orcid":true,"given":"Ahmed A.","family":"Abouelkhair","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02smfhw86","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University","place":["Blacksburg, USA"]},{"id":[{"id":"https:\/\/ror.org\/05p2q6194","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Bacteriology, Mycology, and Immunology, Faculty of Veterinary Medicine, University of Sadat City","place":["Sadat City, Egypt"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1730-4150","authenticated-orcid":true,"given":"Nader S.","family":"Abutaleb","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02smfhw86","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University","place":["Blacksburg, USA"]},{"id":[{"id":"https:\/\/ror.org\/053g6we49","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Immunology, Faculty of Pharmacy, Zagazig University","place":["Zagazig, Egypt"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sahar","family":"Abdelrazek","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02smfhw86","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University","place":["Blacksburg, USA"]},{"name":"Department of Plant Pathology, Faculty of Agriculture, Assiut University","place":["Assiut, Egypt"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0939-0458","authenticated-orcid":true,"given":"Mohamed N.","family":"Seleem","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02smfhw86","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University","place":["Blacksburg, USA"]},{"id":[{"id":"https:\/\/ror.org\/02smfhw86","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for One Health Research, Virginia Polytechnic Institute and State University","place":["Blacksburg, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2478"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro.2016.108"},{"key":"e_1_3_5_4_2","unstructured":"CDC. 2020. 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