Structure-Activity Relationship Studies of a Series of Semisynthetic Lipopeptides Leading to the Discovery of Surotomycin, a Novel Cyclic Lipopeptide Being Developed for the Treatment of Clostridium difficile-Associated Diarrhea.

Abstract

Novel cyclic lipopeptides with different acyl tails were synthesized via a semisynthetic approach. Structure-activity 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 μg/mL) against Clostridium difficile including NAP1 epidemic strains. In hamster efficacy studies, surotomycin protected animals at a dose of 0.5 mg/kg, PO.

• Authors: 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 58 Issue 12 Pg. 5137-42 (Jun 25 2015) ISSN: 1520-4804 [Electronic] United States
• PMID: 25993059 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Lipopeptides
• Peptides, Cyclic

Topics

• Animals
• Anti-Bacterial Agents (chemistry, therapeutic use)
• Clostridioides difficile (drug effects)
• Cricetinae
• Diarrhea (drug therapy, microbiology)
• Enterocolitis, Pseudomembranous (complications, drug therapy)
• Lipopeptides (chemistry, therapeutic use)
• Male
• Microbial Sensitivity Tests
• Peptides, Cyclic (chemistry, therapeutic use)
• Structure-Activity Relationship