Peptidoglycan precursors with D-alanyl-D-alanine terminus (D-Ala-D-Ala) (D-Ala-D-Ala)

Peptidoglycan precursors with a D-alanyl-D-alanine (D-Ala-D-Ala) terminus are essential building blocks in the assembly of the bacterial cell wall, particularly in Gram-positive species (Nature Reviews Microbiology, 2008: https://www.nature.com/articles/nrmicro1825). These precursors, most notably Lipid II, feature a pentapeptide chain ending in the D-Ala-D-Ala dipeptide, which serves as the substrate for transpeptidase enzymes during the cross-linking of the peptidoglycan layer (StatPearls, 2023: https://www.ncbi.nlm.nih.gov/books/NBK459263/). This molecular structure is the specific therapeutic target for glycopeptide antibiotics such as vancomycin and teicoplanin. These drugs bind to the D-Ala-D-Ala terminus through a network of hydrogen bonds, creating a steric block that prevents the incorporation of the precursor into the growing cell wall (PubMed, 2014: https://pubmed.ncbi.nlm.nih.gov/24231350/). This disruption of cell wall synthesis leads to osmotic instability and bacterial cell death. Clinical challenges associated with this target include the emergence of resistant strains, such as Vancomycin-resistant Enterococci (VRE), which modify the terminus to D-alanyl-D-lactate to evade drug binding (NIH, 2019: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604941/).

Other names

D-alanyl-D-alanine terminusLipid II pentapeptidePeptidoglycan pentapeptide terminusD-Ala-D-Ala dipeptide

Inhibition of peptidoglycan polymerization and cross-linking by binding to the D-alanyl-D-alanine terminus of cell wall precursors