D-alanyl-D-alanine terminus of Lipid II and peptidoglycan precursors (D-Ala-D-Ala)

The D-alanyl-D-alanine (D-Ala-D-Ala) terminus is a critical structural component of Lipid II and nascent peptidoglycan precursors in Gram-positive bacteria (Nature Reviews Microbiology, 2008). It serves as the essential substrate for transpeptidase and transglycosylase enzymes, which facilitate the cross-linking and elongation of the bacterial cell wall. By providing the structural framework for the peptidoglycan layer, this dipeptide motif is vital for maintaining bacterial osmotic stability and cell shape. In the context of infectious diseases, it is the primary molecular target for glycopeptide antibiotics such as vancomycin and teicoplanin (PubMed: 11084357). These drugs bind to the D-Ala-D-Ala terminus with high affinity, forming a molecular cap that sterically hinders the enzymatic assembly of the cell wall, ultimately leading to bacterial cell death (StatPearls, Vancomycin). However, the emergence of resistance through the modification of this terminus to D-alanyl-D-lactate (D-Ala-D-Lac) represents a significant clinical challenge in treating multidrug-resistant infections like VRE and VRSA (NIH, 2023).

Other names

D-Ala-D-AlaD-alanyl-D-alanine dipeptidePeptidoglycan pentapeptide terminusLipid II terminusD-Ala-D-Ala motif

Glycopeptide antibiotics bind to the D-Ala-D-Ala terminus of peptidoglycan precursors via five hydrogen bonds, sterically inhibiting the transglycosylation and transpeptidation steps of cell wall synthesis (PubMed: 11084357).