Gong Jun-Jia, Huang I-Hsiu, Hung Yuan-Pin, Chen Yi-Wei, Lin Yun-Chien, Chen Jenn-Wei
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Department of Biochemistry and Microbiology, Oklahoma State University Center for Health Sciences, Tulsa, Oklahoma, USA.
Antimicrob Agents Chemother. 2025 Aug 6;69(8):e0051525. doi: 10.1128/aac.00515-25. Epub 2025 Jun 17.
is an anaerobic, spore-forming pathogen responsible for illnesses ranging from mild diarrhea to life-threatening colitis. 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 strains harbor prophages, we evaluated MMC's potential to enhance antibiotic efficacy against infection (CDI). , 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.
是一种厌氧、形成芽孢的病原体，可导致从轻度腹泻到危及生命的结肠炎等疾病。目前的治疗依赖于万古霉素和甲硝唑（MTZ）等抗生素，但高剂量会破坏肠道微生物群，导致反复感染。丝裂霉素C（MMC）是一种经美国食品药品监督管理局批准的抗癌药物，已知可诱导溶原性细菌中的前噬菌体激活。鉴于超过70%的菌株含有前噬菌体，我们评估了MMC增强抗生素对艰难梭菌感染（CDI）疗效的潜力。结果表明，MMC与MTZ协同作用，抑制R20291菌株以及RT027和RT078临床分离株，同时降低MTZ对生物膜相关细胞的最低杀菌浓度。使用小鼠粪便悬液进行的体外试验证实了联合用药的增强杀菌效果。在小鼠复发模型中，与单一疗法或万古霉素相比，低剂量MTZ + MMC治疗显著提高了生存率并减少了粪便孢子计数。重要的是，该联合用药不会比其他抗生素导致更大的肝或肾毒性，并且导致的结肠上皮损伤更少。微生物群分析显示，与标准治疗相比，MTZ + MMC能更好地保留肠道微生物组成。这些发现表明，低剂量MTZ与MMC联合使用可增强抗菌效果，同时降低毒性和微生物群破坏，为CDI管理提供了一种有前景的策略。
