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

The D-alanyl-D-alanine (D-Ala-D-Ala) terminus is a critical structural component of the peptidoglycan precursors in Gram-positive bacteria (Wikipedia, 2023). It serves as the substrate for transpeptidase enzymes, also known as penicillin-binding proteins, which catalyze the cross-linking of the bacterial cell wall to provide mechanical strength and osmotic protection (StatPearls, 2023). This dipeptide motif is the primary molecular target for glycopeptide antibiotics, such as vancomycin and teicoplanin (PubMed, 2000). By binding to the D-Ala-D-Ala terminus through a specific network of five hydrogen bonds, these drugs sterically inhibit both transglycosylation and transpeptidation, preventing the incorporation of precursors into the growing cell wall (Nature Reviews Microbiology, 2018). This inhibition leads to cell wall instability and subsequent bacterial lysis. Resistance to these drugs typically arises through the metabolic reprogramming of the cell wall synthesis pathway, replacing the terminal D-alanine with D-lactate or D-serine, which drastically reduces antibiotic binding affinity (NIH, 2021).

Other names

D-Ala-D-AlaD-alanyl-D-alaninePeptidoglycan precursor terminusUDP-N-acetylmuramyl-pentapeptide terminusD-alanyl-D-alanine dipeptide

Glycopeptide antibiotics bind to the D-Ala-D-Ala terminus of peptidoglycan precursors via a specific network of hydrogen bonds, sterically hindering the transglycosylation and transpeptidation steps of cell wall synthesis.