D-alanyl-D-alanine terminus (D-Ala-D-Ala) (D-Ala-D-Ala)

The D-alanyl-D-alanine (D-Ala-D-Ala) terminus is a critical structural motif found at the end of the pentapeptide chain of peptidoglycan precursors, such as Lipid II, in the bacterial cell wall [1, 2]. It serves as the essential substrate for penicillin-binding proteins (PBPs), which catalyze the cross-linking of peptidoglycan strands to provide structural integrity to the bacterial cell [5, 18]. Glycopeptide antibiotics, most notably vancomycin, exert their bactericidal effect by forming high-affinity hydrogen bonds with this specific dipeptide motif [2, 6]. This binding sterically blocks the enzymes responsible for polymerization (transglycosylation) and cross-linking (transpeptidation), leading to cell wall instability and osmotic lysis [2, 15]. Resistance to drugs targeting this site typically involves the metabolic reprogramming of the precursor to terminate in D-alanyl-D-lactate or D-alanyl-D-serine, which significantly reduces antibiotic binding affinity [17, 19, 20]. Because this target is unique to bacteria and absent in human cells, it provides a high degree of selectivity for antimicrobial therapy [14, 15].

Other names

Lipid II D-Ala-D-Ala terminusPeptidoglycan pentapeptide terminusAcyl-D-alanyl-D-alanineD-alanyl-D-alanine dipeptidePeptidoglycan precursor terminus

Inhibition of cell wall synthesis by binding to the D-Ala-D-Ala terminus of peptidoglycan precursors, sterically hindering transpeptidase and transglycosylase enzymes.