D-alanyl-D-alanine (D-Ala-D-Ala) terminus of Lipid II (D-Ala-D-Ala)

The D-alanyl-D-alanine (D-Ala-D-Ala) terminus of Lipid II is a critical structural component in the biosynthesis of the bacterial cell wall, specifically within Gram-positive bacteria (NCBI, PMC4862493). Lipid II serves as the essential shuttle molecule that transports peptidoglycan subunits across the cytoplasmic membrane to the growing cell wall (Nature Reviews Microbiology, 2008). The D-Ala-D-Ala dipeptide at the end of the pentapeptide chain is the specific substrate recognized by transpeptidase enzymes to form cross-links that provide the cell wall with mechanical strength (StatPearls, NBK459351). This terminus is the primary molecular target for glycopeptide antibiotics, such as vancomycin, which bind to the dipeptide via a network of five hydrogen bonds (DrugBank, DB00512). By sequestering this substrate, these drugs sterically hinder the transpeptidation and transglycosylation steps of peptidoglycan assembly, ultimately resulting in osmotic lysis and bacterial death (PubMed, 19079146). Resistance to these drugs often involves the metabolic reprogramming of the bacteria to replace the terminal D-alanine with D-lactate or D-serine, which significantly reduces the antibiotic's binding affinity (NIH, PMC2855488). This target is highly conserved among many Gram-positive pathogens, making it a cornerstone of treatment for resistant infections like MRSA.

Other names

D-Ala-D-Ala dipeptideLipid II pentapeptide terminusPeptidoglycan precursor terminus

Glycopeptide antibiotics bind to the D-alanyl-D-alanine terminus of Lipid II, sterically inhibiting the transglycosylation and transpeptidation reactions required for peptidoglycan cross-linking.