D-alanyl-D-alanine terminus of peptidoglycan precursor peptides (D-Ala-D-Ala)

The D-alanyl-D-alanine (D-Ala-D-Ala) terminus is a critical dipeptide motif located at the C-terminal end of the pentapeptide stem of peptidoglycan precursors, such as Lipid II, in bacterial cell walls [1.1.2, 1.4.4]. It serves as the essential substrate for penicillin-binding proteins (PBPs), which catalyze the transpeptidation reactions necessary for cross-linking peptidoglycan strands to maintain structural integrity [1.2.1, 1.4.2]. This motif is the primary therapeutic target for glycopeptide antibiotics, including vancomycin and teicoplanin, which bind to the D-Ala-D-Ala terminus with high affinity through a network of five hydrogen bonds [1.3.2, 1.3.4]. By sequestering this terminus, these drugs sterically inhibit both transglycosylation and transpeptidation, leading to the cessation of cell wall synthesis and subsequent bacterial cell death [1.3.1, 1.4.1]. In the context of disease, this target is vital for the survival of Gram-positive bacteria, making it a focal point for treating severe infections like methicillin-resistant Staphylococcus aureus (MRSA) [1.3.2, 1.3.5]. Resistance often arises when bacteria enzymatically modify this target to D-alanyl-D-lactate or D-alanyl-D-serine, which significantly reduces antibiotic binding affinity [1.2.2, 1.4.3].

Other names

D-Ala-D-Ala terminusD-alanyl-D-alanine dipeptidePeptidoglycan precursor C-terminusAcyl-D-alanyl-D-alanineD-Ala-D-AlaD-alanyl-D-alanine

Inhibition of bacterial cell wall synthesis by binding to the D-Ala-D-Ala terminus of peptidoglycan precursors, which sterically hinders the transpeptidation and transglycosylation steps [1.3.2, 1.3.4].