Formal Single Atom Editing of the Glycosylated Natural Product Fidaxomicin Improves Acid Stability and Retains Antibiotic Activity

Fidaxomicin (Fdx) constitutes a glycosylated natural product with excellent antibacterial activity against various Gram-positive bacteria but is approved only for Clostridioides difficile infections. Poor water solubility and acid lability preclude its use for other infections. Herein, we describe our strategy to overcome the acid lability by introducing acid-stable S-linked glycosides. We describe the direct, diastereoselective modification of unprotected Fdx without the need to avoid air or moisture. Using our newly established approach, Fdx was converted to the single atom exchanged analogue S-Fdx, in which the acid labile O-glycosidic bond to the noviose sugar was replaced by the acid stable S-glycosidic bond. Studies of the antibacterial activity of a structurally diverse set of thioglycoside derivatives revealed high potency of acyl derivatives of S-Fdx against Clostridioides difficile (MIC range: 0.12–4 μg/mL) and excellent potency against Clostridium perfringens (MIC range: 0.06–0.5 μg/mL).

非达霉素（Fidaxomicin, Fdx）是一种糖基化天然产物，对多种革兰氏阳性菌具有优异的抗菌活性，但目前仅被批准用于艰难梭菌（Clostridioides difficile）感染的治疗。其水溶性差且对酸不稳定，限制了其在其他感染性疾病中的应用。本文中，我们报道了通过引入酸稳定的S-连接糖苷来克服其酸不稳定性的策略。我们实现了未保护非达霉素的直接、非对映选择性修饰，且无需隔绝空气与水分。借助我们新建的方法，非达霉素被转化为单原子取代的类似物S-非达霉素（S-Fdx），其中与诺糖相连的酸不稳定O-糖苷键被替换为酸稳定的S-糖苷键。对一系列结构多样的硫糖苷衍生物的抗菌活性研究表明，S-非达霉素的酰基衍生物对艰难梭菌具有高效抗菌活性（最低抑菌浓度范围：0.12–4 μg/mL），对产气荚膜梭菌（Clostridium perfringens）则展现出优异的抗菌活性（最低抑菌浓度范围：0.06–0.5 μg/mL）。