title: Dissecting ramoplanin: mechanistic analysis of synthetic ramoplanin analogues as a guide to the design of improved antibiotics.
abstract: Ramoplanin is a potent cyclic lipoglycodepsipeptide antibiotic that disrupts bacterial cell wall synthesis by binding to the peptidoglycan intermediate Lipid II and blocking its polymerization to form the carbohydrate chains of peptidoglycan. Although ramoplanin is a promising compound for certain indications, it has limitations that impede IV administration for systemic use. However, it may be possible to overcome these limitations with analogues. In this manuscript, we dissect the effects of structural changes to ramoplanin. The studies described here combine total synthesis with enzyme kinetics, NMR analysis, and MIC measurements to shed light on the roles of key structural features in this antibiotic in Lipid II binding, transglycosylation inhibition, and biological activity. The results should serve as a foundation for the design of synthetically accessible analogues with improved biological properties.
authors.affiliation: Department of Chemistry, Princeton University, Princeton, New Jersey 08544, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Chen
authors.forename: Yanqiu
authors.initials: Y
authors.lastname: Yuan
authors.forename: Jeremiah S
authors.initials: JS
authors.lastname: Helm
authors.forename: Yanan
authors.initials: Y
authors.lastname: Hu
authors.forename: Yosup
authors.initials: Y
authors.lastname: Rew
authors.forename: Dongwoo
authors.initials: D
authors.lastname: Shin
authors.forename: Dale L
authors.initials: DL
authors.lastname: Boger
authors.forename: Suzanne
authors.initials: S
authors.lastname: Walker
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002240:Carbohydrate Sequence; D047630:Depsipeptides; D015195:Drug Design; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D047630:Depsipeptides; D010456:Peptides, Cyclic; C041438:ramoplanin