Peptidoglycan D-alanyl-D-alanine (D-Ala-D-Ala) (D-Ala-D-Ala)

Peptidoglycan D-alanyl-D-alanine is a critical dipeptide sequence located at the C-terminus of the pentapeptide side chain of Lipid II, the fundamental building block of the bacterial cell wall (StatPearls, 2023; Wikipedia, 2024). This motif serves as the essential substrate for transpeptidase enzymes, also known as penicillin-binding proteins, which catalyze the cross-linking of peptidoglycan layers to provide structural rigidity and osmotic stability to the bacterial cell (Nature Reviews Microbiology, 2005). In clinical pharmacology, D-alanyl-D-alanine is the primary molecular target for glycopeptide antibiotics such as vancomycin and teicoplanin (PubChem, 2024). These drugs bind to the D-Ala-D-Ala terminus through a specific network of hydrogen bonds, effectively capping the precursor and sterically hindering the transglycosylation and transpeptidation steps of cell wall assembly (PubMed, 2019). This inhibition leads to the cessation of cell wall synthesis, resulting in bacterial cell lysis and death, which is vital for treating severe Gram-positive infections like methicillin-resistant Staphylococcus aureus (MRSA). However, the emergence of resistance through the enzymatic modification of this terminus to D-alanyl-D-lactate or D-alanyl-D-serine significantly reduces drug binding affinity, posing a major therapeutic challenge in managing vancomycin-resistant enterococci (VRE) (NIH, 2021).

Other names

D-alanyl-D-alanine terminusD-Ala-D-Ala dipeptidePeptidoglycan precursor C-terminusLipid II pentapeptide terminus

Glycopeptide antibiotics bind to the D-alanyl-D-alanine terminus of peptidoglycan precursors via five hydrogen bonds, sterically inhibiting the transglycosylation and transpeptidation steps required for cell wall synthesis (StatPearls, 2023; PubMed, 2019).