D-alanyl-D-alanine motif (D-Ala-D-Ala)

The D-alanyl-D-alanine (D-Ala-D-Ala) motif is a critical dipeptide sequence found at the C-terminus of the pentapeptide chain in bacterial peptidoglycan precursors, such as Lipid II (PMID: 11084357). It serves as the essential substrate for transpeptidase enzymes, also known as penicillin-binding proteins, which cross-link the peptidoglycan layers to provide structural integrity and rigidity to the bacterial cell wall (StatPearls, NBK459263). This motif is the primary molecular target for glycopeptide antibiotics, including vancomycin and teicoplanin, which are vital for treating Gram-positive infections (PMID: 15173827). By binding specifically to the D-Ala-D-Ala terminus through five hydrogen bonds, these drugs sterically hinder the transglycosylation and transpeptidation steps of cell wall assembly, ultimately leading to bacterial cell death (PubMed, PMID: 24295361). Clinical resistance often arises through the metabolic substitution of the terminal D-alanine with D-lactate or D-serine, which significantly reduces the binding affinity of the antibiotics (Nature Reviews Microbiology, PMID: 15173827).

Other names

D-Ala-D-Ala terminusD-alanyl-D-alanine dipeptidePeptidoglycan pentapeptide terminusD-alanyl-D-alanine residue

Glycopeptide antibiotics bind to the D-alanyl-D-alanine terminus of the peptidoglycan precursor Lipid II via a network of hydrogen bonds. This binding sterically inhibits the transglycosylation and transpeptidation reactions catalyzed by penicillin-binding proteins (PBPs), thereby preventing the cross-linking of the bacterial cell wall and leading to osmotic lysis (PMID: 11084357; StatPearls, NBK459263).