The design, synthesis and antibiotic activities of the modified carboxylate binding pocket (D-O-E ring) of vancomycin (1) were summarized in this short account. The preliminary Structure-Activity Relationship (SAR) studies indicated that both the structure of the 16-membered macrocycle including the absolute configuration of the modified AA4 unit and the presence of a hydrophobic chain were important for anti-VRE activities of these series of synthetic analogues. Compounds 9c and 9d in which the central amino acid (AA4) of vancomycin was replaced by (2R,3R)-α-hydroxy-β-amino acid and (2R,3R)-α,β-diamino acid, respectively, were found to be useful templates in searching for the active compounds against both vancomycin-sensitive and -resistant strains. Two of these compounds (16d and 16n) having an elongated peptide chain at the C-terminal were found to be active against a broad spectrum of both vancomycin-sensitive (Staphylococcus aureus) and -resistant strains (E. faecium, E. faecalis).