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

The D-alanyl-D-alanine (D-Ala-D-Ala) terminus is a critical structural motif found at the end of the pentapeptide chain of bacterial peptidoglycan precursors, such as Lipid II (StatPearls, 2023). It serves as the substrate for transpeptidase enzymes, also known as penicillin-binding proteins, which catalyze the cross-linking of peptidoglycan layers to provide structural integrity to the bacterial cell wall (PubMed, PMID: 11084358). This terminus is the primary molecular target for glycopeptide antibiotics, including vancomycin, teicoplanin, and newer lipoglycopeptides like dalbavancin (NIH, 2022). By binding specifically to the D-Ala-D-Ala sequence through a series of hydrogen bonds, these drugs sterically hinder the enzymatic assembly of the cell wall, preventing both transglycosylation and transpeptidation, which ultimately leads to bacterial cell lysis (Wikipedia, 2024). Resistance to these antibiotics often arises through the metabolic reprogramming of the cell wall synthesis pathway, resulting in the modification of this target to D-alanyl-D-lactate (D-Ala-D-Lac) or D-alanyl-D-serine (D-Ala-D-Ser), which significantly reduces the binding affinity of the glycopeptides (Nature Reviews Microbiology, 2004).

Other names

D-alanyl-D-alanineD-Ala-D-Ala dipeptidePeptidoglycan pentapeptide terminusLipid II D-Ala-D-Ala 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 stable complex that sterically blocks the transglycosylase and transpeptidase enzymes from accessing the substrate, thereby inhibiting the polymerization and cross-linking of the peptidoglycan layer (PubMed, PMID: 11084358; StatPearls, 2023).