Bacterial peptidoglycan D-alanyl-D-alanine terminus (D-Ala-D-Ala) (D-Ala-D-Ala)

The bacterial peptidoglycan D-alanyl-D-alanine (D-Ala-D-Ala) terminus is a critical structural motif found at the end of the pentapeptide chains of peptidoglycan precursors, such as Lipid II, in Gram-positive bacteria (NCBI: PMC2823387). Its primary biological function is to serve as the substrate for penicillin-binding proteins (PBPs), which catalyze the transpeptidation and transglycosylation reactions necessary for cell wall cross-linking and stability (StatPearls: Vancomycin). In the context of infectious diseases, this terminus is the primary molecular target for glycopeptide antibiotics like vancomycin and teicoplanin (PubMed: 11014201). By forming high-affinity hydrogen bonds with the D-Ala-D-Ala motif, these drugs sterically inhibit the assembly of the bacterial cell wall, leading to cell lysis and death (Nature Reviews Microbiology: 10.1038/nrmicro1170). Resistance to these drugs often involves the enzymatic modification of this target to D-alanyl-D-lactate (D-Ala-D-Lac) or D-alanyl-D-serine, which significantly reduces antibiotic binding affinity (CDC: Antibiotic Resistance). Understanding this target is essential for treating severe infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and other multidrug-resistant Gram-positive pathogens. The specificity of glycopeptides for this bacterial-specific motif ensures minimal direct interaction with host cells, though secondary toxicities can occur.

Other names

D-alanyl-D-alaninePeptidoglycan D-Ala-D-Ala dipeptideC-terminal D-alanyl-D-alanineLipid II D-Ala-D-Ala terminus

Glycopeptide antibiotics bind to the D-alanyl-D-alanine terminus of the peptidoglycan precursor via five hydrogen bonds, sterically hindering the transpeptidase and transglycosylase enzymes from cross-linking the cell wall (StatPearls: Vancomycin; PubMed: 11014201).