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

Abstract

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