Insights into Key Interactions between Vancomycin and Bacterial Cell Wall Structures

Vancomycin is a glycopeptide antibiotic used for the treatment of serious infections by Gram-positive pathogens. Vancomycin inhibits cell wall biosynthesis by targeting the D-Ala-D-Ala terminus of peptidoglycan (PG). The highly cross-linked heptapeptide aglycon structure of vancomycin is the D-Ala-D-Ala binding site. The first residue of vancomycin is N-methyl-leucine, which is crucial for the dipeptide binding. The removal of N-methyl-leucine by Edman degradation results in desleucyl-vancomycin devoid of antimicrobial activities. To investigate the function of N-methyl-leucine for the dipeptide binding in vancomycin, molecular dynamics simulations of vancomycin and three N-terminus-modified vancomycin derivatives: desleucyl-vancomycin, vancomycin(NtoC), and vancomycin(Sar), binding to a PG unit of the sequence L-Ala-D-iso-Gln-L-Lys-D-Ala-D-Ala with an intact pentaglycine bridge structure attached to the bridge link of L-Lys were carried out. Glycopeptide-PG binding interactions were characterized by root-mean-square-deviation contour analysis of atomic positions in vancomycin and its three analogues bound to a PG unit. The overall sampling space for four glycopeptide-PG complexes shows four distinct distributions with a continuous change between the conformational spaces. The hydrogen bond analyses show that multiple hydrogen bonds between the D-Ala-D-Ala and the vancomycin aglycon structure strengthened the dipeptide binding. The simulations revealed that the removal or chemical modification of N-methyl-leucine significantly weakens the dipeptide binding to the aglycon structure and provides interesting structural insights into glycopeptide-PG binding interactions.