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

Peptidoglycan precursor D-alanyl-D-alanine is a critical structural component of the bacterial cell wall, specifically found at the C-terminus of the pentapeptide chain in peptidoglycan precursors such as Lipid II (PubChem CID 439531). This dipeptide serves as the essential substrate for transpeptidase enzymes, also known as penicillin-binding proteins, which facilitate the cross-linking of peptidoglycan layers to provide mechanical strength and osmotic stability to the bacterial cell (StatPearls, "Vancomycin"). In clinical pharmacology, D-alanyl-D-alanine is the primary molecular target for glycopeptide antibiotics, including vancomycin and teicoplanin. These antibiotics bind to the D-Ala-D-Ala terminus through a network of five hydrogen bonds, sterically hindering both the transglycosylation and transpeptidation steps of cell wall synthesis, which ultimately leads to bacterial cell death (PubMed: 10657237). Resistance to these agents, particularly in Enterococcus species, typically arises from the enzymatic modification of the target to D-alanyl-D-lactate or D-alanyl-D-serine, which drastically reduces the binding affinity of the antibiotic (Nature Reviews Microbiology, 2003). This target is central to the management of serious Gram-positive infections, including those caused by methicillin-resistant Staphylococcus aureus (MRSA). Therapeutic monitoring of drugs hitting this target is often required due to potential side effects like nephrotoxicity and the risk of selecting for resistant strains (NIH, "Vancomycin").

Other names

D-alanyl-D-alanine terminusPeptidoglycan D-Ala-D-Ala terminusD-Ala-D-Ala dipeptideC-terminal D-alanyl-D-alaninePeptidoglycan pentapeptide terminusLipid II D-Ala-D-Ala terminus

Glycopeptide antibiotics bind to the D-Ala-D-Ala terminus of peptidoglycan precursors, sterically inhibiting the transglycosylation and transpeptidation reactions required for cell wall assembly.