title: 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.affiliation: †Merck and Co., Inc., Kenilworth, New Jersey 07033, United States.
authors.forename: Ning
authors.initials: N
authors.lastname: Yin
authors.affiliation: †Merck and Co., Inc., Kenilworth, New Jersey 07033, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: †Merck and Co., Inc., Kenilworth, New Jersey 07033, United States.
authors.forename: Yong
authors.initials: Y
authors.lastname: He
authors.affiliation: †Merck and Co., Inc., Kenilworth, New Jersey 07033, United States.
authors.forename: Prudencio
authors.initials: P
authors.lastname: Herradura
authors.affiliation: †Merck and Co., Inc., Kenilworth, New Jersey 07033, United States.
authors.forename: Andre
authors.initials: A
authors.lastname: Pearson
authors.affiliation: †Merck and Co., Inc., Kenilworth, New Jersey 07033, United States.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Mesleh
authors.affiliation: †Merck and Co., Inc., Kenilworth, New Jersey 07033, United States.
authors.forename: Carmela T
authors.initials: CT
authors.lastname: Mascio
authors.affiliation: †Merck and Co., Inc., Kenilworth, New Jersey 07033, United States.
authors.forename: Karen
authors.initials: K
authors.lastname: Howland
authors.affiliation: †Merck and Co., Inc., Kenilworth, New Jersey 07033, United States.
authors.forename: Judith
authors.initials: J
authors.lastname: Steenbergen
authors.affiliation: †Merck and Co., Inc., Kenilworth, New Jersey 07033, United States.
authors.forename: Grace M
authors.initials: GM
authors.lastname: Thorne
authors.affiliation: ‡R.M. Alden Research Lab, 6133 Bristol Parkway Ste 175, Culver City, California 90230, United States.
authors.forename: Diane
authors.initials: D
authors.lastname: Citron
authors.affiliation: †Merck and Co., Inc., Kenilworth, New Jersey 07033, United States.
authors.forename: Andrew D G
authors.initials: AD
authors.lastname: Van Praagh
authors.affiliation: †Merck and Co., Inc., Kenilworth, New Jersey 07033, United States.
authors.forename: Lawrence I
authors.initials: LI
authors.lastname: Mortin
authors.affiliation: †Merck and Co., Inc., Kenilworth, New Jersey 07033, United States.
authors.forename: Dennis
authors.initials: D
authors.lastname: Keith
authors.affiliation: †Merck and Co., Inc., Kenilworth, New Jersey 07033, United States.
authors.forename: Jared
authors.initials: J
authors.lastname: Silverman
authors.affiliation: †Merck and Co., Inc., Kenilworth, New Jersey 07033, United States.
authors.forename: Chester
authors.initials: C
authors.lastname: Metcalf
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000627:therapeutic use*; D016360:Clostridioides difficile / Q000187:drug effects*; D006224:Cricetinae; D003967:Diarrhea / Q000188:drug therapy* / Q000382:microbiology; D004761:Enterocolitis, Pseudomembranous / Q000150:complications / Q000188:drug therapy*; D055666:Lipopeptides / Q000737:chemistry* / Q000627:therapeutic use*; D008297:Male; D008826:Microbial Sensitivity Tests; D010456:Peptides, Cyclic / Q000737:chemistry / Q000627:therapeutic use; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D055666:Lipopeptides; D010456:Peptides, Cyclic