The Roles of Dimerization and Membrane Anchoring in Activity of Glycopeptide Antibiotics against Vancomycin-Resistant Bacteria

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 bind 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 H-1 NMR spectroscopy, we demonstrate enhanced binding due to dimerization and propose that this enhancement will act cooperatively with membrane anchoring in biphenylchloroeremomycin.