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Clostridioides difficile is the leading cause of hospital-associated diarrhea and has remained a consistent threat for older patients and those with comorbidities or vulnerabilities. The high rates of treatment failure and recurrence, along with the decreased effectiveness of first-line treatments highlight the urgent need for the development of new anti-C. difficile agents. α-mangostin is a natural compound isolated from the edible mangosteen fruit pericarps that has known antimicrobial activity. α-mangostin is poorly absorbed from the gastrointestinal tract (GIT), which is ideal for treatment of CDI to accumulate at the site of infection at concentrations capable of clearing C. difficile. We found that α-mangostin was as potent as the standard-of-care vancomycin, inhibiting a diverse panel of C. difficile strains at a concentration range of 0.5–2 µg/mL. It exhibited rapid bactericidal activity, completely clearing C. difficile in vitro within 2 hours, surpassing vancomycin and fidaxomicin. Additionally, α-mangostin’s anti-C. difficile activity was not affected by the high C. difficile inoculum. To further understand its mechanism, we investigated α-mangostin’s membrane disruption activity by assessing the leakage of DNA and ATP post-exposure. α-mangostin resulted in a significant leakage of DNA and ATP indicating that its anti-C. difficile activity is mediated by the bacterial cell membrane disruption. Collectively, these findings demonstrate that α-mangostin possesses desirable characteristics for a promising anti-C. difficile which merits further investigation.

艰难梭菌（Clostridioides difficile）是引发医院相关性腹泻的首要致病菌，始终对老年患者、合并基础疾病或存在生理脆弱状态的人群构成持续威胁。该菌的治疗失败率与复发率居高不下，且一线治疗方案的疗效逐年下降，这凸显了研发新型抗艰难梭菌制剂的迫切需求。
α-倒捻子素（α-mangostin）是一种从可食用山竹果皮中分离得到的天然化合物，已被证实具有抗菌活性。该物质在胃肠道（gastrointestinal tract, GIT）中吸收率极低，这一特性恰好适配艰难梭菌感染（CDI）的治疗需求，可在感染部位聚集至足以清除艰难梭菌的有效浓度。
本研究发现，α-倒捻子素的抗菌效力与临床标准治疗药物万古霉素相当，可在0.5~2 μg/mL的浓度范围内抑制多种艰难梭菌菌株。其展现出快速杀菌活性，可在2小时内完全清除体外培养的艰难梭菌，疗效优于万古霉素与非达霉素（fidaxomicin）。此外，α-倒捻子素的抗艰难梭菌活性不受高接种量艰难梭菌的影响。
为进一步阐明其抗菌机制，本研究通过检测药物处理后细菌胞内DNA与ATP的泄漏情况，探究了α-倒捻子素的细胞膜破坏活性。实验结果显示，α-倒捻子素可引发细菌胞内DNA与ATP的显著泄漏，表明其抗艰难梭菌活性是通过破坏细菌细胞膜实现的。
综上，本研究结果表明α-倒捻子素具备成为新型抗艰难梭菌制剂的理想特质，值得开展进一步的深入研究。