D-alanyl-D-alanine (D-Ala-D-Ala) motif of lipid II (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 Lipid II, the essential precursor for bacterial peptidoglycan synthesis (NCBI, NBK459359). In Gram-positive bacteria, this dipeptide serves as the substrate for transpeptidase enzymes, which facilitate the cross-linking of glycan strands to provide mechanical strength to the cell wall (PubMed, 11084357). Because this motif is unique to bacteria and absent in eukaryotic cells, it represents a highly effective therapeutic target for glycopeptide antibiotics such as vancomycin (StatPearls, NBK459359). These drugs bind to the D-Ala-D-Ala terminus through a network of hydrogen bonds, forming a stable complex that sterically inhibits the assembly of the peptidoglycan layer (PubMed, 15157411). This disruption leads to the loss of cell wall integrity, resulting in bacterial cell death through osmotic lysis (PubMed, 24295360). Resistance to drugs targeting this motif often arises through the substitution of the terminal D-alanine with D-lactate or D-serine, which significantly reduces the binding affinity of traditional glycopeptides (PubMed, 10601204). Newer lipoglycopeptides like oritavancin have been developed to overcome these resistance mechanisms by providing additional binding interactions with the bacterial membrane (PubMed, 24295360). Overall, the D-Ala-D-Ala motif remains a cornerstone target in the treatment of serious infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and other Gram-positive pathogens (StatPearls, NBK459359).

Other names

D-Ala-D-Ala terminusD-alanyl-D-alanine dipeptideLipid II pentapeptide terminusPeptidoglycan precursor D-Ala-D-Ala

Glycopeptide antibiotics bind to the D-Ala-D-Ala C-terminus of the peptidoglycan precursor Lipid II via five hydrogen bonds (PubMed, 15157411). This binding creates a steric shield that prevents the transglycosylase and transpeptidase enzymes from accessing the substrate to incorporate it into the growing peptidoglycan chain, thereby inhibiting cell wall synthesis (StatPearls, NBK459359).