The roles of dimerization and membrane anchoring in activity of glycopeptide antibiotics against vancomycin-resistant bacteria

Gary J. Sharman, Andrew C. Try, Robert J. Dancer, Younghoon R. Cho, Thomas Staroske, Ben Bardsley, Alison J. Maguire, Matthew A. Cooper, Dominic P. O'Brien, Dudley H. Williams*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

65 Citations (Scopus)

Abstract

The mode of action of a semisynthetic glycopeptide active against vancomycin-resistant bacteria has been investigated. It is shown that the antibiotic, biphenylchloroeremomycin or LY307599, dimerizes strongly and anchors to membranes. It is hypothesized that these two locating devices, previously identified by us when acting separately, might combine to give enhanced binding at a cell surface. This hypothesis is tested experimentally by showing that glycopeptides can brad cell-wall precursor analogues from resistant bacteria (terminating in -D-lactate) in a similar manner to those from susceptible bacteria (terminating in -D-alanine) and by using model cell surfaces where the benefits of dimerization can be expressed and studied. These model systems use vesicles to represent the cell membrane, to which cell wall analogues are anchored via a docosanoyl chain, so mimicking the arrangement encountered at the cell surface. Using 1H NMR spectroscopy, we demonstrate enhanced binding due to dimerization and propose that this enhancement will act cooperatively with membrane anchoring in biphenylchloroeremomycin.

Original languageEnglish
Pages (from-to)12041-12047
Number of pages7
JournalJournal of the American Chemical Society
Volume119
Issue number50
DOIs
Publication statusPublished - 17 Dec 1997

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