D-Alanyl-D-alanine terminus of peptidoglycan (D-Ala-D-Ala) (D-Ala-D-Ala)

The D-Alanyl-D-alanine (D-Ala-D-Ala) terminus is a critical molecular motif found on the pentapeptide side chains of peptidoglycan precursors in Gram-positive bacteria (Nature Reviews Microbiology, 2017). It serves as the essential substrate for transpeptidase enzymes, also known as penicillin-binding proteins, which catalyze the cross-linking of the bacterial cell wall to provide structural rigidity and osmotic protection (PubMed, 2019). This terminus is the primary pharmacological target for glycopeptide antibiotics, such as vancomycin and teicoplanin. By forming a complex of five hydrogen bonds with the D-Ala-D-Ala motif, these drugs sterically hinder the incorporation of the precursor into the growing peptidoglycan polymer (StatPearls, 2023). This inhibition leads to a weakened cell wall, resulting in bacterial cell lysis and death. Resistance to these drugs typically involves the metabolic reprogramming of the cell wall synthesis pathway to replace the terminal D-alanine with D-lactate or D-serine, which drastically reduces the binding affinity of the antibiotic (Nature Reviews Microbiology, 2017). This target is unique to bacteria, making it an ideal site for selective toxicity in antimicrobial therapy. Understanding the structural nuances of this terminus has led to the development of second-generation lipoglycopeptides with enhanced potency against resistant strains.

Other names

D-alanyl-D-alanine dipeptidePeptidoglycan precursor terminusD-Ala-D-Ala motifLipid II pentapeptide terminus

Glycopeptide antibiotics bind to the D-Ala-D-Ala terminus of the peptidoglycan precursor (Lipid II) via five hydrogen bonds, sterically inhibiting the transglycosylation and transpeptidation reactions required for cell wall cross-linking (StatPearls, 2023; Journal of Biological Chemistry, 2006).