D-Alanyl-D-alanine dipeptide terminus of bacterial peptidoglycan (D-Ala-D-Ala)

The D-Alanyl-D-alanine dipeptide terminus is a structural motif on the pentapeptide stem of bacterial peptidoglycan, found at the ends of nascent peptidoglycan precursors. This motif is generated in the cytoplasm by D-Ala-D-Ala ligase and is essential for the elongation and cross-linking of peptidoglycan, which gives bacteria their mechanical strength and protects against osmotic lysis. The D-Ala-D-Ala motif is the direct binding site of glycopeptide antibiotics such as vancomycin, whose mechanism of action involves prevention of cell wall synthesis by blocking transpeptidase-mediated crosslinking. The motif is also the molecular mimic for β-lactam antibiotics, which inhibit the crosslinking enzymes (transpeptidases). Replacement of the terminal D-Ala with D-Lactate (D-Ala-D-Lac) confers intrinsic or acquired resistance to vancomycin in certain bacteria. The D-Ala-D-Ala motif is not a protein, enzyme, or receptor, but a carbohydrate-linked dipeptide recognized as a key drug target in infectious disease therapy and antibiotic resistance research.

Other names

D-alanyl-D-alanineD-Ala-D-Ala endD-Ala-D-Ala terminusPeptidoglycan pentapeptide terminus

Vancomycin binds directly to D-Ala-D-Ala termini, blocking transpeptidation and cell wall synthesis, causing bacterial cell death\nBeta-lactam antibiotics mimic D-Ala-D-Ala and irreversibly inhibit transpeptidases responsible for crosslinking peptidoglycan\nD-cycloserine inhibits D-Ala-D-Ala ligase, depleting precursor availability for cell wall biosynthesis