Peptidoglycan precursors terminating in D-alanyl-D-alanine (D-Ala-D-Ala)

Peptidoglycan precursors terminating in D-alanyl-D-alanine (D-Ala-D-Ala) are essential intermediates in the biosynthesis of the bacterial cell wall, primarily in Gram-positive bacteria (NCBI, 2023). These precursors, such as Lipid II, feature a pentapeptide chain that ends in the D-Ala-D-Ala dipeptide, which is the critical substrate for cross-linking enzymes. This specific molecular motif serves as the primary target for glycopeptide antibiotics like vancomycin and teicoplanin (PubMed, 2019). By binding to the D-Ala-D-Ala terminus, these drugs form a steric 'cap' that prevents transglycosylases and transpeptidases from incorporating the precursor into the growing peptidoglycan polymer. This disruption leads to a weakened cell wall, osmotic instability, and eventual bacterial cell death. Clinical resistance often arises through the enzymatic modification of this target to D-alanyl-D-lactate or D-alanyl-D-serine, which significantly reduces the binding affinity of traditional glycopeptide drugs (Nature Reviews Microbiology, 2017).

Other names

D-alanyl-D-alanine terminusPeptidoglycan pentapeptide terminusLipid II D-Ala-D-Ala terminusD-Ala-D-Ala

Glycopeptide antibiotics bind to the D-Ala-D-Ala terminus of peptidoglycan precursors via five hydrogen bonds, sterically hindering the transglycosylation and transpeptidation reactions necessary for cell wall assembly (StatPearls, 2023).