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

The D-alanyl-D-alanine (D-Ala-D-Ala) terminus is a critical structural motif found on the pentapeptide side chains of peptidoglycan precursors, such as Lipid II, in Gram-positive bacteria like Streptococcus pneumoniae (StatPearls, 2023). This dipeptide 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 structural integrity of the bacterial cell wall (Nature Reviews Microbiology, 2006). Glycopeptide antibiotics, including vancomycin and teicoplanin, exert their bactericidal effect by binding with high affinity to the D-Ala-D-Ala terminus through a network of five hydrogen bonds (PubMed, PMID: 16921300). This interaction creates a steric cap that blocks the enzymes responsible for polymerizing and cross-linking the cell wall, leading to osmotic instability and cell death (Journal of Biological Chemistry, 2008). Because this target is located on the exterior of the cytoplasmic membrane, it is highly accessible to drugs, though therapeutic challenges include the emergence of resistance through the modification of the terminus to D-alanyl-D-lactate (StatPearls, 2023).

Other names

D-alanyl-D-alanineD-Ala-D-Ala dipeptidePeptidoglycan pentapeptide terminusLipid II C-terminus

Glycopeptide antibiotics bind to the D-Ala-D-Ala terminus of peptidoglycan precursors via hydrogen bonding, sterically hindering the transglycosylation and transpeptidation reactions required for cell wall assembly.