D-alanyl-D-alanine terminus of bacterial peptidoglycan precursors (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 bacterial peptidoglycan precursors, such as Lipid II (PubChem, https://pubchem.ncbi.nlm.nih.gov/compound/Vancomycin). It serves as the essential substrate for transpeptidase enzymes, also known as penicillin-binding proteins, which cross-link the peptidoglycan layers to provide structural rigidity to the bacterial cell wall (StatPearls, https://www.ncbi.nlm.nih.gov/books/NBK459263/). This terminus is the primary molecular target for glycopeptide antibiotics, including vancomycin and teicoplanin, which bind to the D-Ala-D-Ala moiety through a specific network of five hydrogen bonds (Nature Scientific Reports, https://www.nature.com/articles/srep13168). By capping this terminus, these drugs sterically hinder the enzymatic processes of transglycosylation and transpeptidation, leading to the arrest of cell wall assembly and subsequent bacterial death (StatPearls, 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 produce D-alanyl-D-lactate or D-alanyl-D-serine termini, which drastically reduces the binding affinity of the drugs (Microbiology Society, https://www.microbiologyresearch.org/content/journal/micro/10.1099/mic.0.26306-0). This target is specifically relevant for treating infections caused by Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA).

Other names

D-alanyl-D-alanineD-Ala-D-Ala dipeptidePeptidoglycan C-terminusLipid II terminusD-alanyl-D-alanine moiety

Glycopeptide antibiotics bind to the D-Ala-D-Ala terminus via hydrogen bonding, sterically hindering the transglycosylation and transpeptidation steps of peptidoglycan synthesis.