The synthesis and binding of N-terminal derivatives of vancomycin to a bacterial cell wall analogue

We report the synthesis of novel derivatives of the glycopeptide antibiotic vancomycin, modified at the N-terminus. Binding constants were measured for the association of these derivatives with the tripeptide analogue N,N-diacetyl-L-lysyl-D-alanyl-D-alanine. Replacement of the sp(3) centre of the leucine residue of vancomycin with an sp(2) centre resulted in weaker binding in all cases. These findings contrast with the relatively strong binding of some of the analogous derivatives previously obtained from ristocetin A. The reduction in the binding affinities of the vancomycin derivatives is attributed to a conformational change in the antibiotic which is not possible in the analogous derivatives of the aglycone of ristocetin.