Terminal D-alanyl-D-alanine motif of peptidoglycan precursors (D-Ala-D-Ala)

The terminal D-alanyl-D-alanine (D-Ala-D-Ala) motif is a critical structural component of the peptidoglycan precursors in the cell walls of Gram-positive bacteria. It serves as the substrate for transpeptidase enzymes, also known as penicillin-binding proteins, which catalyze the cross-linking of peptidoglycan chains to provide mechanical strength to the bacterial cell wall (StatPearls, 2023). This motif is the primary target for glycopeptide antibiotics, such as vancomycin and teicoplanin, which bind to the dipeptide via five hydrogen bonds (Nature Reviews Microbiology, 2017). By sequestering the D-Ala-D-Ala terminus, these drugs sterically hinder the enzymes responsible for cell wall polymerization and cross-linking, leading to bacterial cell lysis and death. Resistance to these antibiotics often involves the modification of this target, where the terminal D-alanine is replaced by D-lactate or D-serine, significantly reducing the binding affinity of the drug (Journal of Biological Chemistry, 2014). Understanding this motif is essential for the development of next-generation antibiotics designed to overcome bacterial resistance mechanisms.

Other names

D-alanyl-D-alanine terminusD-Ala-D-Ala dipeptidePeptidoglycan pentapeptide terminusD-Ala-D-Ala motif

Glycopeptide antibiotics bind to the D-alanyl-D-alanine terminus of peptidoglycan precursors through hydrogen bonding, sterically inhibiting the transglycosylation and transpeptidation steps required for cell wall assembly.