Structure鈥揂ctivity Relationship Studies of a Series of Semisynthetic Lipopeptides Leading to the Discovery of Surotomycin, a Novel Cyclic Lipopeptide Being Developed for the Treatment of Clostridiu

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• 作者：Ning Yin ; Jing Li ; Yong He ; Prudencio Herradura ; Andre Pearson ; Michael F. Mesleh ; Carmela T. Mascio ; Karen Howland ; Judith Steenbergen ; Grace M. Thorne ; Diane Citron ; Andrew D. G. Van Praagh ; Lawrence I. Mortin ; Dennis Keith ; Jared Silverman ; Chester Metcalf
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：June 25, 2015
• 年：2015
• 卷：58
• 期：12
• 页码：5137-5142
• 全文大小：457K
• ISSN：1520-4804

文摘

Novel cyclic lipopeptides with different acyl tails were synthesized via a semisynthetic approach. Structure鈥揳ctivity relationship studies revealed that lipophilicity, chain length, and the location of key aromatic functionalities of the tail modulated activity. The lead compound surotomycin exhibited significantly improved in vitro activity compared with daptomycin (MIC₉₀ 0.5 vs 2 渭g/mL) against Clostridium difficile including NAP1 epidemic strains. In hamster efficacy studies, surotomycin protected animals at a dose of 0.5 mg/kg, PO.