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

The Peptidoglycan terminal D-alanyl-D-alanine (D-Ala-D-Ala) is a critical structural motif found at the C-terminus of the pentapeptide chain in bacterial peptidoglycan precursors, such as Lipid II (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC452202/). It serves as the essential substrate for transpeptidase enzymes, also known as penicillin-binding proteins, which catalyze the cross-linking of peptidoglycan layers to provide mechanical strength and osmotic stability to the bacterial cell wall (https://pubchem.ncbi.nlm.nih.gov/compound/Vancomycin). This motif is the primary molecular target for glycopeptide antibiotics, most notably vancomycin and teicoplanin (https://www.ncbi.nlm.nih.gov/books/NBK459263/). These drugs bind to the D-Ala-D-Ala terminus through a specific network of five hydrogen bonds, forming a stable complex that sterically hinders the transglycosylation and transpeptidation steps of cell wall assembly (https://www.nature.com/articles/s41467-019-12113-2). This inhibition leads to the cessation of cell wall synthesis, resulting in bacterial cell lysis and death, particularly in Gram-positive pathogens like Staphylococcus aureus and Enterococcus species (https://www.ncbi.nlm.nih.gov/books/NBK459263/). Clinical resistance to these antibiotics often involves the metabolic reprogramming of the cell wall synthesis pathway to replace the terminal D-alanine with D-lactate or D-serine, which drastically reduces the binding affinity of the drugs (https://mmbr.asm.org/content/69/2/191).

Other names

D-alanyl-D-alaninePeptidoglycan pentapeptide terminusLipid II terminus

Inhibition of peptidoglycan synthesis by binding to the D-Ala-D-Ala terminus of cell wall precursors, preventing transglycosylation and transpeptidation.