Peptidoglycan pentapeptide D-alanyl-D-alanine terminus (D-Ala-D-Ala)

The peptidoglycan pentapeptide D-alanyl-D-alanine (D-Ala-D-Ala) terminus is a fundamental structural element found in the cell wall precursors, specifically Lipid II, of Gram-positive bacteria (Nature Reviews Microbiology, 2008). Its primary biological function is to serve as a substrate for transpeptidase enzymes, also known as penicillin-binding proteins (PBPs), which facilitate the cross-linking of peptidoglycan layers (Journal of Biological Chemistry, 2011). This cross-linking is essential for maintaining the structural integrity and osmotic stability of the bacterial cell wall. In the context of infectious diseases, this terminus is the specific molecular target for the glycopeptide class of antibiotics, including vancomycin and teicoplanin (StatPearls, 2023). These drugs bind to the D-Ala-D-Ala motif through a highly specific network of five hydrogen bonds, effectively capping the precursor (PubMed, 2019). This binding sterically hinders the enzymes responsible for transglycosylation and transpeptidation, thereby halting cell wall synthesis and leading to bacterial cell death. Clinical challenges associated with this target include the emergence of resistance, where bacteria replace the terminal D-alanine with D-lactate or D-serine, drastically reducing drug affinity (Microbiology and Molecular Biology Reviews, 2005). Understanding this target is crucial for developing next-generation lipoglycopeptides designed to overcome such resistance mechanisms.

Other names

D-alanyl-D-alanineD-Ala-D-AlaPeptidoglycan precursor pentapeptideLipid II pentapeptide terminus

Glycopeptide antibiotics bind to the D-alanyl-D-alanine terminus of the peptidoglycan precursor via five hydrogen bonds, sterically inhibiting the transglycosylation and transpeptidation steps of cell wall synthesis (StatPearls, 2023).