D-alanyl-D-alanine terminus of bacterial cell wall peptidoglycan precursors (D-Ala-D-Ala)

The D-alanyl-D-alanine (D-Ala-D-Ala) terminus is a critical structural component of the peptidoglycan precursors in Gram-positive bacteria, specifically found on the pentapeptide side chain of Lipid II (NCBI, PMC4711158). It serves as the essential substrate for transpeptidase enzymes, also known as penicillin-binding proteins, which catalyze the cross-linking of peptidoglycan layers to maintain the mechanical integrity of the bacterial cell wall (StatPearls, NBK459358). This dipeptide motif is the primary molecular target for glycopeptide antibiotics, including vancomycin and teicoplanin (PubMed, 11581571). By forming five hydrogen bonds with the D-Ala-D-Ala terminus, these antibiotics sterically hinder the enzymes responsible for transglycosylation and transpeptidation, thereby halting cell wall assembly (Nature Reviews Microbiology, 2017). This disruption results in osmotic instability and bacterial cell death. Resistance mechanisms, such as those seen in Vancomycin-resistant Enterococci (VRE), involve the substitution of the terminal D-alanine with D-lactate, which drastically reduces the binding affinity of the antibiotic (CDC, 2019). Newer lipoglycopeptides like dalbavancin and oritavancin also target this site but feature additional mechanisms to enhance potency and overcome certain resistance phenotypes (PubMed, 24015197). This target remains a cornerstone of therapy for serious Gram-positive infections, although its utility is increasingly challenged by evolving bacterial resistance strategies.

Other names

D-Ala-D-AlaD-alanyl-D-alaninePeptidoglycan pentapeptide terminusLipid II D-Ala-D-Ala terminusC-terminal D-alanyl-D-alanine

Glycopeptide antibiotics bind with high affinity to the D-alanyl-D-alanine C-terminus of the peptidoglycan precursor Lipid II. This binding sterically inhibits the transglycosylation (polymerization of the sugar backbone) and transpeptidation (cross-linking of peptide chains) steps of cell wall synthesis, leading to cell wall weakening and bacterial lysis (StatPearls, NBK459358; PubMed, 11581571).