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

The Bacterial peptidoglycan D-alanyl-D-alanine (D-Ala-D-Ala) terminus is a critical structural motif found at the C-terminal end of the pentapeptide stem in peptidoglycan precursors, such as Lipid II, and in nascent peptidoglycan chains [1, 3, 13]. It serves as the essential substrate for penicillin-binding proteins (PBPs), which utilize the energy from the cleavage of the terminal D-alanine to catalyze the cross-linking of peptidoglycan strands [5, 14, 20]. This cross-linking process is vital for maintaining the mechanical strength and osmotic stability of the bacterial cell wall [15, 16, 17]. The D-Ala-D-Ala terminus is the specific molecular target for glycopeptide antibiotics, including vancomycin, teicoplanin, and newer lipoglycopeptides like dalbavancin [1, 2, 6]. These drugs bind to the D-Ala-D-Ala motif through a network of hydrogen bonds, effectively sequestering the substrate from enzymatic processing [2, 4, 7]. This binding sterically hinders both transglycosylase and transpeptidase enzymes, leading to the inhibition of cell wall assembly and subsequent bacterial cell death [1, 5, 21]. Resistance to these antibiotics often involves the enzymatic replacement of the terminal D-alanine with D-lactate or D-serine, which significantly reduces the binding affinity of the drugs [2, 8, 11, 18]. Because this target is unique to bacteria, drugs affecting it exhibit high selective toxicity with minimal impact on host cells [4, 14].

Other names

D-alanyl-D-alanine dipeptideD-Ala-D-Ala motifPeptidoglycan precursor terminusAcyl-D-alanyl-D-alanine terminusC-terminal D-Ala-D-Ala

Glycopeptide antibiotics bind to the D-alanyl-D-alanine terminus of peptidoglycan precursors, sequestering the substrate and sterically inhibiting the transglycosylation and transpeptidation steps of cell wall synthesis [1, 2, 4, 5, 7, 8, 14, 21].