Antibiotic activities and affinities for bacterial cell wall analogue of N-demethylvancomycin and its derivatives

Abstract

N-Demethylvancomycin, which has been clinically used in China, is one member of vancomycin group (glycopeptide) antibiotics. It differs from vancomycin only in that methyl group on the amino group of the N-terminal residue of vancomycin has been replaced by H. By reductive alkylation of N-demethylvancomycin, we synthesized N-alkyl and N,N'-dialkyl N-demethylvancomycins, which closely correlated with vancomycin in structure. The association constants of the complexes of N-demethylvancomycin and its analogues with di-N-Ac-L-Lys-D-Ala-D-Ala and the antibiotic activity against Staphylococcus aureus of the glycopeptides were determined. Results showed that N-demethylvancomycin has higher affinity for bacterial cell wall analogue di-N-Ac-L-Lys-D-Ala-D-Ala and more potent antibiotic activity against Staphylococcus aureus than vancomycin. Both N-alkylation and N,N'-dialkylation of N-demethylvancomycin reduced the affinity and antibiotic activity. The longer the alkyl groups, the less potent antibiotic activities and lower affinities have the glycopeptides. The antibiotic activities against Staphylococcus aureus of N-demethylvancomycin and its analogues roughly parallel their affinities for di-N-Ac-L-Lys-D-Ala-D-Ala.