Dissecting ramoplanin: mechanistic analysis of synthetic ramoplanin analogues as a guide to the design of improved antibiotics.
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.
Chen
Lan
L
Department of Chemistry, Princeton University, Princeton, New Jersey 08544, USA.
Yuan
Yanqiu
Y
Helm
Jeremiah S
JS
Hu
Yanan
Y
Rew
Yosup
Y
Shin
Dongwoo
D
Boger
Dale L
DL
Walker
Suzanne
S
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
D000900:Anti-Bacterial Agents; D047630:Depsipeptides; D010456:Peptides, Cyclic; C041438:ramoplanin