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

The 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 in Gram-positive bacteria (Nature Reviews Microbiology, 2008). It serves as the essential substrate for penicillin-binding proteins (PBPs), which catalyze the transpeptidation and transglycosylation reactions necessary for bacterial cell wall cross-linking and stability (StatPearls, 2023). This motif is the primary therapeutic target for glycopeptide antibiotics, such as vancomycin and teicoplanin (PubChem, 2024). These drugs bind to the D-Ala-D-Ala terminus through a network of five hydrogen bonds, creating a molecular cap that sterically hinders the enzymatic assembly of the cell wall (Journal of Biological Chemistry, 1994). Disruption of this process leads to cell wall weakening and eventual osmotic lysis of the bacterium. Resistance to these drugs often involves the metabolic reprogramming of the cell wall synthesis pathway to replace the terminal D-alanine with D-lactate or D-serine, which significantly reduces drug binding affinity by removing a key hydrogen bond (Nature Reviews Microbiology, 2008).

Other names

D-alanyl-D-alanine dipeptidePeptidoglycan pentapeptide terminusUDP-N-acetylmuramyl-pentapeptide terminusD-Ala-D-Ala motif

Glycopeptide antibiotics bind to the D-Ala-D-Ala terminus via a network of hydrogen bonds, which sterically hinders the transglycosylation and transpeptidation enzymes (penicillin-binding proteins) from incorporating the precursor into the peptidoglycan layer (StatPearls, 2023; Nature Reviews Microbiology, 2008).