D-Alanyl-D-alanine terminus of bacterial cell wall precursor (D-Ala-D-Ala terminus)

The D-Alanyl-D-alanine terminus of bacterial cell wall precursors is a dipeptide motif located at the end of the peptidoglycan pentapeptide in the cell wall precursors of most Gram-positive and some Gram-negative bacteria. This motif is essential for cross-linking peptidoglycan strands, a process critical for maintaining bacterial cell wall strength and integrity. Many antibiotics, notably glycopeptides such as vancomycin, exert their activity by binding tightly to the D-Ala-D-Ala terminus, thereby sterically blocking enzymes required for peptidoglycan cross-linking and inhibiting cell wall biosynthesis, which leads to bactericidal activity. Resistance to these drugs often arises through modification of the target terminus, most commonly via substitution of D-Ala-D-Lac in pathogenic bacteria, drastically reducing drug binding and efficacy. The D-Ala-D-Ala motif is not present in mammalian cells, making it a selective and valuable point of therapeutic intervention for bacterial infections.

Other names

D-Ala-D-AlaD-alanyl-D-alanine terminusD-alanyl-D-alanine dipeptidepeptidoglycan pentapeptide terminuscell wall precursor D-Ala-D-Ala

Drugs like vancomycin bind the D-Ala-D-Ala terminus, sterically blocking peptidoglycan cross-linking enzymes (transglycosylase and transpeptidase) and inhibiting cell wall synthesis, leading to bacterial cell death. β-lactam antibiotics mimic the D-Ala-D-Ala structure and irreversibly acylate the active site serine of transpeptidases, blocking cell wall cross-linking. D-cycloserine inhibits D-alanine racemase and D-Ala-D-Ala ligase, blocking D-Ala-D-Ala synthesis.