A modified vancomycin binding pocket (D-O-E ring) incorporating an alpha -hydroxy-beta -amino acid at the AA4 position is designed and synthesized. Some of these compds. display potent bioactivities against both sensitive- and resistant-strains (8 micro g/mL against VREF). Both the lipidated aminoglucose and the structure of the 16-membered macrocycle are found to be important for the anti-VRE activities. The polyamine appendage at the C-terminal, on the other hand, improved the activity against vancomycin-sensitive strains. [on SciFinder (R)]