Peptidoglycan precursor D-alanyl-D-alanine terminus (D-Ala-D-Ala)

The Peptidoglycan precursor D-alanyl-D-alanine (D-Ala-D-Ala) terminus is a critical structural motif found in the cell wall precursors of Gram-positive bacteria. It serves as the substrate for transpeptidase enzymes, also known as penicillin-binding proteins, which facilitate the cross-linking of peptidoglycan chains to provide mechanical strength to the bacterial cell wall (PubChem: https://pubchem.ncbi.nlm.nih.gov/compound/Vancomycin). This terminus is the primary molecular target for glycopeptide antibiotics, such as vancomycin and teicoplanin. By binding to the D-Ala-D-Ala dipeptide, these drugs sterically hinder the assembly of the cell wall, leading to cell death. Resistance to these antibiotics often arises through 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 drug binding affinity (Journal of Biological Chemistry: https://www.jbc.org/article/S0021-9258(17)46763-1/fulltext). Understanding this target is essential for the development of next-generation antibiotics capable of overcoming resistant bacterial strains.

Other names

D-alanyl-D-alanineD-Ala-D-Ala dipeptidePeptidoglycan C-terminal D-Ala-D-AlaLipid II D-Ala-D-Ala terminusUDP-N-acetylmuramoyl-pentapeptide D-Ala-D-Ala

Glycopeptide antibiotics bind with high affinity to the D-alanyl-D-alanine C-terminus of the peptidoglycan precursor (Lipid II) via a network of five hydrogen bonds (StatPearls: https://www.ncbi.nlm.nih.gov/books/NBK459263/). This binding sterically inhibits the transglycosylation and transpeptidation reactions catalyzed by penicillin-binding proteins (PBPs), thereby preventing the cross-linking of the peptidoglycan layer and leading to bacterial cell lysis (Nature Reviews Microbiology: https://www.nature.com/articles/nrmicro1166).