Elucidation of the active conformation of vancomycin dimers with antibacterial activity against vancomycin-resistant bacteria

Jun Nakamura, Hidenori Yamashiro, Sayaka Hayashi, Mami Yamamoto, Kenji Miura, Shu Xu, Takayuki Doi, Hideki Maki, Osamu Yoshida, Hirokazu Arimoto

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

Abstract

Covalently linked vancomycin dimers have attracted a great deal of attention among researchers because of their enhanced antibacterial activity against vancomycin-resistant strains. However, the lack of a clear insight into the mechanisms of action of these dimers hampers rational optimization of their antibacterial potency. Here, we describe the synthesis and antibacterial activity of novel vancomycin dimers with a constrained molecular conformation achieved by two tethers between vancomycin units. Conformational restriction is a useful strategy for studying the relationship between the molecular topology and biological activity of compounds. In this study, two vancomycin units were linked at three distinct positions of the glycopeptide (vancosamine residue (V), C terminus (C), and N terminus (N)) to form two types of novel vancomycin cyclic dimers. Active NC-VV-linked dimers with a stable conformation as indicated by molecular mechanics calculations selectively suppressed the peptidoglycan polymerization reaction of vancomycin-resistant Staphylococcus aureus in vitro. In addition, double-disk diffusion tests indicated that the antibacterial activity of these dimers against vancomycin-resistant enterococci might arise from the inhibition of enzymes responsible for peptidoglycan polymerization. These findings provide a new insight into the biological targets of vancomycin dimers and the conformational requirements for efficient antibacterial activity against vancomycin-resistant strains. Squashing superbugs: Conformationally constrained vancomycin dimers that inhibit the peptidoglycan synthesis of vancomycin-resistant bacteria were prepared (see scheme). The potent antibacterial activity of the dimers was suggested to arise from their direct action on transglycosylase enzymes.

Original languageEnglish
Pages (from-to)12681-12689
Number of pages9
JournalChemistry - A European Journal
Volume18
Issue number40
DOIs
Publication statusPublished - 2012 Oct 1

Keywords

  • antibiotics
  • conformational restriction
  • dimers
  • structure-activity relationships
  • vancomycin

ASJC Scopus subject areas

  • Catalysis
  • Organic Chemistry

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