Binding of glycopeptide antibiotics to a model of a vancomycin-resistant bacterium

AbstractBackground: The vancomycin group of glycopeptide antibiotics is active against a wide range of gram-positive bacteria. The increasing resistance to vancomycin is the result of a change of an amide linkage (d-Ala-d-Ala) to an ester linkage (d-Ala-d-Lactate) in the bacterial cell-wall precursors.Results: We have used a peptide terminating in the sequence -Lys-d-Ala-d-Lactate linked by its amino terminus to a docosanoyl (C22) acyl chain and anchored in a supported lipid monolayer to mimic the surface of vancomycin-resistant enterococci. Surface plasmon resonance analysis was then used to investigate the binding of glycopeptide group antibiotics to this surface. Vancomycin, which dimerises weakly, bound with low affinity, whereas strongly dimerising antibiotics, such as chloroeremomycin, bound with higher affinities. Antibiotics that have attached hydrophobic groups, such as teicoplanin and biphenylchloroeremomycin (LY307599), bound to the lipid monolayer. This resulted in an enhanced affinity for the lipid-anchored peptide at the surface relative to affinities for an analogous non-anchored peptide in solution.Conclusions: We have shown that the affinities of glycopeptide antibiotics for a model of the surface of a vancomycin-resistant bacterium are enhanced relative to affinities determined in free solution. We have also shown that antibiotics that have membrane anchors bind tightly to the model surface and that this feature is an important determinant of the ability of an antibiotic to kill vancomycin-resistant enterococci