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

The D-alanyl-D-alanine (D-Ala-D-Ala) terminus of the peptidoglycan precursor lipid II is a critical structural motif in the assembly of the Gram-positive bacterial cell wall (Source: Nature Reviews Microbiology, 2008). Lipid II serves as the essential carrier that transports peptidoglycan subunits across the cytoplasmic membrane to the site of cell wall synthesis. The D-Ala-D-Ala dipeptide at the end of the pentapeptide chain is the specific substrate recognized by transpeptidase enzymes, also known as penicillin-binding proteins, which catalyze the cross-linking of the peptidoglycan layer. This terminus is the primary molecular target for glycopeptide antibiotics, such as vancomycin and teicoplanin (Source: StatPearls, 2023). By binding with high affinity to this dipeptide via five hydrogen bonds, these drugs sterically hinder the enzymatic reactions required for cell wall polymerization, ultimately leading to bacterial cell death. Resistance to these antibiotics often involves the modification of this target to D-alanyl-D-lactate or D-alanyl-D-serine, which significantly reduces drug binding affinity (Source: Clinical Microbiology Reviews, 2019). This target is unique to bacteria, providing a high degree of selective toxicity for therapeutic intervention.

Other names

D-Ala-D-AlaD-alanyl-D-alanine dipeptidePeptidoglycan precursor terminusLipid II D-Ala-D-Ala

Glycopeptide antibiotics bind to the D-alanyl-D-alanine terminus of the peptidoglycan precursor lipid II via five hydrogen bonds. This binding sterically inhibits the transglycosylation and transpeptidation steps of peptidoglycan synthesis, preventing the cross-linking of the bacterial cell wall and leading to cell lysis (Source: StatPearls, 2023).