D-alanyl-D-alanine (D-Ala-D-Ala) terminus of bacterial peptidoglycan (D-Ala-D-Ala)

The D-alanyl-D-alanine (D-Ala-D-Ala) terminus of bacterial peptidoglycan is a critical structural component found in the cell wall precursors of Gram-positive bacteria (StatPearls, 2023). It serves as the substrate for transpeptidase enzymes, also known as penicillin-binding proteins, which cross-link peptidoglycan chains to provide mechanical strength to the bacterial cell wall (PubMed, PMID: 10601206). This specific dipeptide sequence is the primary molecular target for glycopeptide antibiotics such as vancomycin and teicoplanin (DrugBank, DB00512). By forming a complex of five hydrogen bonds with the D-Ala-D-Ala terminus, vancomycin sterically inhibits both the transglycosylation and transpeptidation steps of cell wall assembly (Nature, 2017). This disruption leads to cell wall weakening and eventual osmotic lysis of the bacterium, making it a potent bactericidal target. 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 (NIH, 2021). This modification significantly reduces the binding affinity of glycopeptides, leading to the emergence of vancomycin-resistant strains like VRE and VRSA.

Other names

D-Ala-D-AlaPeptidoglycan D-alanyl-D-alanine terminusLipid II D-Ala-D-Ala terminusBacterial cell wall precursor terminusVancomycin binding site

Inhibition of bacterial cell wall synthesis by binding to the D-alanyl-D-alanine terminus of peptidoglycan precursors, which sterically hinders transpeptidation and transglycosylation reactions (StatPearls, 2023; PubMed, PMID: 10601206).