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Current treatments rely on antibiotics such as vancomycin and metronidazole (MTZ), but high doses can disrupt gut microbiota, contributing to recurrent infections. Mitomycin C (MMC), a Food and Drug Administration-approved anticancer agent, is known to induce prophage activation in lysogenic bacteria. Given that over 70% of\n                      <jats:italic toggle=\"yes\">C. difficile<\/jats:italic>\n                      strains harbor prophages, we evaluated MMC\u2019s potential to enhance antibiotic efficacy against\n                      <jats:italic toggle=\"yes\">C. difficile<\/jats:italic>\n                      infection (CDI).\n                      <jats:italic toggle=\"yes\">In vitro<\/jats:italic>\n                      , MMC synergized with MTZ to inhibit strain R20291 and clinical isolates of RT027 and RT078 while reducing the minimum bactericidal concentration of MTZ against biofilm-associated cells. Ex vivo assays using mouse fecal suspensions confirmed the enhanced killing effect of the combination. In a murine recurrence model, low-dose MTZ + MMC treatment significantly improved survival and reduced fecal spore counts compared to monotherapies or vancomycin. Importantly, the combination did not cause greater liver or kidney toxicity than other antibiotics and resulted in less colonic epithelial damage. Microbiota profiling revealed that MTZ + MMC better preserved gut microbial composition than standard treatments. These findings suggest that low-dose MTZ combined with MMC enhances antimicrobial efficacy while reducing toxicity and microbiota disruption, offering a promising strategy for CDI management.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.00515-25","type":"journal-article","created":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T05:49:46Z","timestamp":1750139386000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":2,"title":["Combination of mitomycin C and low-dose metronidazole synergistically against\n                    <i>Clostridioides difficile<\/i>\n                    infection and recurrence prevention"],"prefix":"10.1128","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-1937-3757","authenticated-orcid":false,"given":"Jun-Jia","family":"Gong","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01b8kcc49","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University","place":["Tainan, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I-Hsiu","family":"Huang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02mfxdp77","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biochemistry and Microbiology, Oklahoma State University Center for Health Sciences","place":["Tulsa, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1006-705X","authenticated-orcid":true,"given":"Yuan\u2011Pin","family":"Hung","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01b8kcc49","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University","place":["Tainan, Taiwan"]},{"id":[{"id":"https:\/\/ror.org\/01b8kcc49","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Internal Medicine, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University","place":["Tainan, Taiwan"]},{"id":[{"id":"https:\/\/ror.org\/01b8kcc49","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medicine, College of Medicine, National Cheng Kung University","place":["Tainan, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Wei","family":"Chen","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/046rm7j60","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Oral Biology and Medicine, School of Dentistry, University of California","place":["Los Angeles, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun-Chien","family":"Lin","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01b8kcc49","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University","place":["Tainan, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5433-5178","authenticated-orcid":true,"given":"Jenn-Wei","family":"Chen","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01b8kcc49","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University","place":["Tainan, Taiwan"]},{"id":[{"id":"https:\/\/ror.org\/01b8kcc49","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University","place":["Tainan, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_4_2_2","first-page":"168","article-title":"Clostridioides difficile infection: update on management","volume":"101","author":"Mounsey A","year":"2020","unstructured":"Mounsey A, Lacy Smith K, Reddy VC, Nickolich S. 2020. 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