D-alanyl-D-alanine dipeptide terminus (D-Ala-D-Ala) (D-Ala-D-Ala)

The D-alanyl-D-alanine (D-Ala-D-Ala) dipeptide terminus is a critical molecular component of the nascent peptidoglycan layer in Gram-positive bacteria. It serves as the essential substrate for transpeptidase enzymes, also known as penicillin-binding proteins (PBPs), which catalyze the cross-linking of peptidoglycan chains to provide the bacterial cell wall with structural integrity and osmotic stability (StatPearls, 2023). This dipeptide motif is the primary target for glycopeptide antibiotics, such as vancomycin and teicoplanin, which bind to the terminus via a network of five hydrogen bonds (PubMed, PMC452202). This binding event creates a steric shield that prevents the incorporation of the precursor into the growing cell wall and inhibits the subsequent cross-linking of the peptidoglycan layer. The inhibition of these transglycosylation and transpeptidation steps ultimately leads to bacterial cell death through lysis (NIH, 2022). Resistance to these antibiotics is a significant clinical challenge, often mediated by the substitution of the terminal D-alanine with D-lactate or D-serine. This modification reduces the binding affinity of glycopeptides by up to 1000-fold, rendering the drugs ineffective against resistant strains like Vancomycin-resistant Enterococci (Nature, 2017). Understanding this target is vital for the development of next-generation lipoglycopeptides designed to overcome such resistance mechanisms.

Other names

D-alanyl-D-alanineD-Ala-D-Ala terminusPeptidoglycan pentapeptide terminusUDP-MurNAc-pentapeptide terminus

Inhibition of bacterial cell wall synthesis by binding to the D-Ala-D-Ala terminus, which sterically blocks transglycosylation and transpeptidation.