Identification of synthetic compounds active against VRE: the role of the lipidated aminoglucose and the structure of glycopeptide binding pocket

Synthesis of modified vancomycin binding pocket (D–O–E ring) incorporating a ( R)- or ( S)-configured secondary alcohol function at the AA4 position is described. The presence of both the lipidated aminoglucose (part A) and the structure of the 16-membered macrocycle (part B) are important for the observed activities of the modified vancomycin D–O–E ring against VRE. The polyamine appendage at the C-terminal (part C), on the other hand, improved the activity against vancomycin-sensitive strains. A modified vancomycin binding pocket (D–O–E ring) incorporating an α-hydroxy-β-amino acid at the AA4 position is designed and synthesized. Some of these compounds display potent bioactivities against both sensitive- and resistant-strains (8 μg/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.