D-alanyl-D-alanine peptide motif of peptidoglycan precursor

The D-alanyl-D-alanine peptide motif of peptidoglycan precursor is a dipeptide sequence that forms the terminal part of the stem peptide in the peptidoglycan subunits of most bacteria. This motif is essential for the cross-linking reactions that build and maintain bacterial cell wall structural integrity, with the cross-linking catalyzed by transpeptidase enzymes during peptidoglycan biosynthesis. The D-Ala-D-Ala terminus serves as a critical binding site for glycopeptide antibiotics like vancomycin, which inhibits cell wall synthesis by binding this motif and preventing further polymerization and cross-linking—resulting in bacterial cell death. Modifications of this motif, such as replacement with D-Ala-D-Lac or D-Ala-D-Ser, confer resistance to vancomycin and related drugs and are a key mechanism underlying antibiotic resistance in clinically relevant pathogens. The D-Ala-D-Ala motif is not present in humans, making it an effective and selective antimicrobial target.

Other names

D-Ala-D-Ala motifD-alanyl-D-alanine terminusD-alanine–D-alanine dipeptide motifD-Ala–D-AlaD-alanyl–D-alanine

Inhibition of cell wall cross-linking by non-covalent binding to D-Ala-D-Ala motif (glycopeptide antibiotics, e.g., vancomycin); Competitive inhibition of transpeptidase (β-lactam antibiotics, by mimicking D-Ala-D-Ala but not binding D-Ala-D-Ala directly)