L-Lysyl-D-alanyl-D-alanine terminus of peptidoglycan precursor (Lys-D-Ala-D-Ala)

The L-Lysyl-D-alanyl-D-alanine (Lys-D-Ala-D-Ala) terminus is a critical structural component of the peptidoglycan precursor, specifically found in the cell walls of many Gram-positive bacteria (StatPearls, NBK459363). It serves as the substrate for penicillin-binding proteins (PBPs), which catalyze the cross-linking of peptidoglycan chains to provide mechanical strength to the bacterial cell wall (Nature Reviews Microbiology, 2017). This terminus is the primary molecular target for glycopeptide antibiotics, such as vancomycin and teicoplanin. These drugs bind to the D-Ala-D-Ala dipeptide with high affinity, physically blocking the enzymes responsible for cell wall assembly (PubMed, 29075017). Disruption of this process leads to weakened cell walls and eventual osmotic lysis of the bacteria. Resistance to these antibiotics often involves the modification of this target to D-Ala-D-Lac or D-Ala-D-Ser, which significantly reduces drug binding affinity (NIH, PMC4522021). This target is unique to bacteria, providing a high degree of selective toxicity for antimicrobial therapy.

Other names

D-Ala-D-Ala terminusPeptidoglycan pentapeptide terminusLipid II C-terminusD-Alanyl-D-alanine

Glycopeptide antibiotics bind to the D-Ala-D-Ala terminus of the peptidoglycan precursor through five hydrogen bonds. This binding sterically inhibits the transglycosylation and transpeptidation steps of cell wall synthesis, preventing the cross-linking of the peptidoglycan layer and leading to bacterial cell lysis (StatPearls, NBK459363; Nature Reviews Microbiology, 2017).