The anaerobic, gastrointestinal pathogen Clostridioides difficile can cause severe forms of enterocolitis which is mainly mediated by the toxins it produces. The RNA polymerase inhibitor Fidaxomicin is the current gold standard for the therapy of C. difficile infections due to several beneficial features including its ability to suppress toxin synthesis in C. difficile. In contrast to the Rifamycins, Fidaxomicin binds to the RNA polymerase switch region, which is also the binding site for Myxopyronin B. Here, serial broth dilution assays were performed to test the susceptibility of C. difficile and other anaerobes to Myxopyronin B, proving that the natural product is considerably active against C. difficile and that there is no cross-resistance between Fidaxomicin and Myxopyronin B in a Fidaxomicin-resistant C. difficile strain. Moreover, mass spectrometry analysis indicated that Myxopyronin B is able to suppress early phase toxin synthesis in C. difficile to the same degree as Fidaxomicin. Conclusively, Myxopyronin B is proposed as a new lead structure for the design of novel antibiotics for the therapy of C. difficile infections.

中文翻译：

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Myxopyronin B 抑制 Fidaxomicin 抗性艰难梭菌分离物的生长并干扰毒素合成

厌氧性胃肠道病原体艰难梭菌可引起严重形式的小肠结肠炎，这主要由其产生的毒素介导。RNA 聚合酶抑制剂 Fidaxomicin 是目前治疗艰难梭菌感染的金标准，因为它具有多种有益特性，包括其抑制艰难梭菌毒素合成的能力。与利福霉素相比，非达霉素与 RNA 聚合酶开关区域结合，该区域也是粘菌素 B 的结合位点。在这里，进行连续肉汤稀释测定以测试艰难梭菌和其他厌氧菌对粘菌素 B 的敏感性，证明该天然产物对艰难梭菌具有相当大的活​​性，并且在对非达霉素耐药的艰难梭菌菌株中，非达霉素和 Myxopyronin B 之间没有交叉耐药性。而且，质谱分析表明，Myxopyronin B 能够以与 Fidaxomicin 相同的程度抑制艰难梭菌的早期毒素合成。最终，提出了 Myxopyronin B 作为一种新的先导结构，用于设计用于治疗艰难梭菌感染的新型抗生素。