Attempted introduction of a fourth amide NH into the carboxylate-binding pocket of glycopeptide antibiotics

We report the synthesis of a novel derivative of the glycopeptide antibioti c vancomycin, modified at the N-terminus. This incorporates a fourth amide NH into the antibiotic, at the position which was formerly the N-terminus o f the antibiotic-binding pocket. Although this modification gives the poten tial to form an extra hydrogen bond to the carboxylate anion of the bacteri al cell-wall precursor analogue (N,N)-diacetyl-L-lysyl-D-alanyl-D-alanine, the modified antibiotic does not show enhanced binding to this precursor. T his lack of enhanced binding is associated with an unfavourable conformatio nal change (relative to the desired conformation) in the antibiotic.