Nuclear magnetic resonance studies on the interaction of avoparcin with model receptors of bacterial cell walls.

On the basis of nuclear Overhauser enhancement and 1H chemical shift data obtained in aqueous solution, a model is proposed for the interaction of beta-avoparcin and epi-beta-avoparcin with acetyl-D-alanyl-D-alanine (Ac-D-Ala-D-Ala) and diacetyl-L-lysyl-D-alanyl-D-alanine (Ac2-L-Lys-D-Ala-D-Ala). For the beta-avoparcin: Ac2-L-Lys-D-Ala-Ala complex, the COOH-terminal end of the tripeptide is located near the NH2 terminus of the antibiotic with the tripeptide extending across the peptide backbone of beta-avoparcin toward its COOH-terminal end. In our proposed structure, the three amino acid residues of the peptide span the entire length of the antibiotic, and the aliphatic side chain of the lysine residue extends over the D-ring of beta-avoparcin. The structure of the epi-beta-avoparcin:Ac2-L-Lys-D-Ala-D-Ala complex was found to be similar to the beta-avoparcin complex at the binding site for the lysine residue at the COOH-terminal end of the antibiotic, but differed in the interactions at the NH2 terminus. These results are consistent with the similarities in the COOH-terminal conformations and the differences in conformations at the NH2 terminus found for beta-avoparcin and epi-beta-avoparcin which were described in the preceding paper [Fesik, S. W., I. M. Armitage, G. A. Ellestad, and W. J. McGahren, Mol. Pharmacol. 25:275-280 (1984)]. The association constants (measured by UV methods) for both beta-avoparcin:peptide complexes were greater than those measured for epi-beta-avoparcin and correlated with their differences in antibacterial activity. Epi-beta-avoparcin exhibited no measurable binding to the dipeptide: however, a significant affinity was measured for the tripeptide, indicating that the interactions with the NH2 terminus of the antibiotics provide binding energy for the antibiotic peptide complex but that the COOH-terminal end of the antibiotics also plays an important role in the binding interaction. These results are interesting in light of the similarities in the structural and conformational features at the COOH terminus for all of the glycopeptide antibiotics.