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

The D-alanyl-D-alanine (D-Ala-D-Ala) terminus is a critical structural motif found in the peptidoglycan precursors of Gram-positive bacteria, specifically within Lipid II and the pentapeptide chain (NCBI, NBK459359). It serves as the substrate for transpeptidase enzymes, also known as penicillin-binding proteins, which cross-link the peptidoglycan layers to provide mechanical strength to the bacterial cell wall (PubMed, 16119961). This terminus is the primary molecular target for glycopeptide antibiotics, such as vancomycin and teicoplanin, which bind to the D-Ala-D-Ala dipeptide through a network of hydrogen bonds (StatPearls, NBK459359). By sequestering this motif, these drugs sterically hinder the enzymatic reactions required for cell wall assembly, leading to bacterial cell lysis and death (PubChem, CID 14969). Resistance to these antibiotics often arises through the modification of this terminus to D-alanyl-D-lactate (D-Ala-D-Lac), which significantly reduces the binding affinity of the drugs (PubMed, 10640681). Understanding this target is essential for treating serious infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and other multidrug-resistant Gram-positive pathogens. The specificity of glycopeptides for this bacterial-specific motif minimizes direct interference with human cellular processes, although secondary toxicities can occur. Newer lipoglycopeptides like dalbavancin and oritavancin also target this site but include additional mechanisms to enhance potency and overcome certain resistance phenotypes.

Other names

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

Glycopeptide antibiotics bind to the D-Ala-D-Ala terminus via five hydrogen bonds, sterically inhibiting the transglycosylation and transpeptidation steps of peptidoglycan synthesis (StatPearls, NBK459359).