The Role of Phenolic Groups in Vancomycin-Type Glycopeptide Antibiotics

The complexes of vancomycin group antibiotics with peptides are stabilized by hydrogen bonding and hydrophobic interactions. Association is sharply reduced at high pH. The basis for this pH effect has been examined to discover whether hydrogen bonding between phenolic hydroxyl groups of the antibiotic and carbonyl groups of the binding peptide contributes to complex stabilization. A high-field NMR study of the glycopeptide antibiotic ψ-aglycoristocetin (1) and its complexes with the bacterial cell-wall mimetic peptides Ac-D-ala-D-ala (2), methyl succinyl-D-ala-D-ala (3), and Ac2-L-lys-D-ala-D-ala (4) has been carried out in methanol at low temperature so that the phenolic proton signals could be observed individually. The 1H chemical shifts of the phenolic protons were very sensitive to the structure of the complexes but no evidence was found for strong hydrogen bonds between the peptides and any of the phenols. It is concluded that sharply decreased peptide binding of 1 and related antibiotics at high pH is due to ionization of the phenols leading to electrostatic repulsion between the antibiotic and the negatively charged peptide.