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Dissecting ramoplanin: mechanistic analysis of synthetic ramoplanin analogues as a guide to the design of improved antibiotics

Academic Article
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Overview

authors

  • Chen, L.
  • Yuan, Y. Q.
  • Helm, J. S.
  • Hu, Y. N.
  • Rew, Y.
  • Shin, D. W.
  • Boger, Dale
  • Walker, S.

publication date

  • June 2004

journal

  • Journal of the American Chemical Society  Journal

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.

subject areas

  • Anti-Bacterial Agents
  • Bacteria
  • Carbohydrate Sequence
  • Depsipeptides
  • Drug Design
  • Microbial Sensitivity Tests
  • Models, Biological
  • Molecular Sequence Data
  • Molecular Structure
  • Peptides, Cyclic
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Identity

International Standard Serial Number (ISSN)

  • 0002-7863

Digital Object Identifier (DOI)

  • 10.1021/ja047879t

PubMed ID

  • 15198592
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Additional Document Info

start page

  • 7462

end page

  • 7463

volume

  • 126

issue

  • 24

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