Bacterial peptidoglycan precursor D-alanyl-D-alanine terminus (D-Ala-D-Ala) (D-Ala-D-Ala)

The bacterial peptidoglycan precursor D-alanyl-D-alanine (D-Ala-D-Ala) terminus is a critical structural component in the biosynthesis of the Gram-positive bacterial cell wall. It serves as the substrate for transpeptidase enzymes, also known as penicillin-binding proteins, which cross-link peptidoglycan chains to provide the cell wall with mechanical strength and osmotic stability (StatPearls, 2023). This dipeptide terminus is the primary molecular target for glycopeptide antibiotics, including vancomycin, teicoplanin, and newer lipoglycopeptides like dalbavancin. By binding to the D-Ala-D-Ala motif through a network of hydrogen bonds, these drugs sterically hinder the transglycosylation and transpeptidation steps of peptidoglycan assembly, leading to bacterial cell lysis (PubMed, PMID: 11014214). Because this specific D-amino acid configuration is unique to bacteria and absent in mammalian cells, it represents a highly selective target for antimicrobial therapy. However, the clinical utility of targeting this site is threatened by the emergence of resistance, where bacteria modify the terminus to D-alanyl-D-lactate or D-alanyl-D-serine, significantly reducing antibiotic binding affinity (Nature Reviews Microbiology, 2004).

Other names

D-alanyl-D-alaninePeptidoglycan pentapeptide C-terminusD-Ala-D-Ala dipeptideUDP-N-acetylmuramyl-pentapeptide terminus

Glycopeptide antibiotics bind to the D-alanyl-D-alanine terminus of the peptidoglycan precursor (Lipid II) via five hydrogen bonds. This binding forms a physical barrier that prevents transglycosylases from polymerizing the glycan chains and transpeptidases from cross-linking the peptide side chains, resulting in a compromised cell wall and subsequent bacterial death (StatPearls, 2023; PubMed, PMID: 11014214).