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

The D-alanyl-D-alanine (D-Ala-D-Ala) motif is a critical structural component found at the C-terminus of the pentapeptide chain in peptidoglycan precursors, most notably Lipid II, in Gram-positive bacteria (PubMed, 2014). It serves as the essential substrate for penicillin-binding proteins (PBPs), which catalyze the cross-linking of the bacterial cell wall to provide mechanical stability and protect the cell from osmotic pressure. This motif is the primary therapeutic target for glycopeptide antibiotics, such as vancomycin, which bind to the dipeptide via a specific binding pocket. By sequestering the D-Ala-D-Ala terminus, these drugs sterically hinder the enzymes responsible for peptidoglycan polymerization and cross-linking, ultimately leading to cell wall weakening and osmotic lysis (StatPearls, 2023). Resistance to these drugs often arises through the modification of this motif to D-alanyl-D-lactate (D-Ala-D-Lac) or D-alanyl-D-serine (D-Ala-D-Ser), which significantly reduces antibiotic binding affinity (Journal of Biological Chemistry, 2014). Understanding this target is vital for treating serious infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and other multi-drug resistant Gram-positive pathogens.

Other names

D-Ala-D-Ala motifD-alanyl-D-alanine dipeptideLipid II D-Ala-D-Ala terminusPeptidoglycan pentapeptide terminusD-alanyl-D-alanine moiety

Glycopeptide antibiotics bind to the D-Ala-D-Ala C-terminus of the pentapeptide chain of Lipid II and nascent peptidoglycan via a network of five hydrogen bonds. This binding sterically inhibits the transglycosylation (polymerization) and transpeptidation (cross-linking) steps of cell wall synthesis, leading to the cessation of cell wall construction and subsequent bacterial cell death (StatPearls, 2023; Nature Reviews Microbiology, 2008).