Peptidoglycan precursor D-alanyl-D-alanine terminus on Lipid II (D-Ala-D-Ala on Lipid II)

The D-alanyl-D-alanine (D-Ala-D-Ala) terminus on Lipid II is a fundamental structural component in the biosynthesis of the bacterial peptidoglycan layer (NCBI, PMC2830643). Lipid II acts as a carrier molecule that transports peptidoglycan subunits across the cytoplasmic membrane to the cell exterior (Nature Reviews Microbiology, 2005). The D-Ala-D-Ala dipeptide at the end of the pentapeptide chain is the specific molecular target for glycopeptide antibiotics such as vancomycin (StatPearls, 2023). By binding to this terminus, these drugs sterically hinder the enzymes responsible for polymerizing and cross-linking the cell wall, specifically transglycosylases and transpeptidases (PubMed, 11544347). This inhibition results in a weakened cell wall, making the bacteria susceptible to osmotic lysis. This target is highly conserved among Gram-positive bacteria but is shielded by the outer membrane in most Gram-negative species. Resistance to drugs targeting this site typically involves the metabolic reprogramming of the terminus to D-alanyl-D-lactate, which drastically reduces the binding affinity of glycopeptides (NEJM, 1994).

Other names

Lipid II D-Ala-D-Ala terminusD-alanyl-D-alanine dipeptidePeptidoglycan precursor Lipid IIBacterial cell wall precursor Lipid II

Glycopeptide antibiotics bind to the D-alanyl-D-alanine terminus of the Lipid II pentapeptide via five hydrogen bonds (PubMed, 11544347). This binding sterically inhibits the transglycosylation and transpeptidation reactions required for peptidoglycan cross-linking, leading to cell wall degradation and bacterial death (StatPearls, 2023).