Peptidoglycan D-alanyl-D-alanine terminus (D-Ala-D-Ala) (D-Ala-D-Ala)

The Peptidoglycan D-alanyl-D-alanine terminus is a critical structural component of the bacterial cell wall precursor, specifically found at the C-terminal end of the pentapeptide chain (StatPearls, 2023). This dipeptide motif serves as the substrate for transpeptidase enzymes (penicillin-binding proteins) that catalyze the cross-linking of peptidoglycan layers, providing mechanical strength to the bacterial cell wall (NCBI, 2022). It is the primary molecular target for glycopeptide antibiotics, such as vancomycin and teicoplanin, which bind to the D-Ala-D-Ala moiety via a network of five hydrogen bonds (PubMed, 2021). By sequestering this terminus, these drugs sterically hinder the enzymatic assembly of the cell wall, leading to bacterial cell lysis and death (Nature, 2020). This target is predominantly relevant in Gram-positive bacteria, as the outer membrane of Gram-negative bacteria typically prevents glycopeptide penetration. Resistance to drugs targeting this site often involves the metabolic reprogramming of the cell wall synthesis pathway to replace the terminal D-alanine with D-lactate or D-serine, significantly reducing drug binding affinity (Microbiology Society, 2019).

Other names

D-alanyl-D-alanineD-Ala-D-Ala dipeptidePeptidoglycan precursor C-terminusUDP-N-acetylmuramyl-pentapeptide terminus

Glycopeptide antibiotics bind with high affinity to the D-alanyl-D-alanine C-terminus of the peptidoglycan precursor, sterically inhibiting the transglycosylation and transpeptidation reactions required for cell wall cross-linking (StatPearls, 2023; PubMed, 2021).