Peptidoglycan D-alanyl-D-alanine terminus and pentaglycine cross-link (D-Ala-D-Ala/Pentaglycine)

Peptidoglycan is an essential polymer that forms a mesh-like layer outside the plasma membrane of most bacteria, providing structural strength and protection against osmotic lysis (PubMed, PMID: 18476318). The D-alanyl-D-alanine (D-Ala-D-Ala) terminus is a critical structural motif found on the peptide stems of peptidoglycan precursors, such as Lipid II, and nascent peptidoglycan chains in Gram-positive bacteria (StatPearls, NBK459358). Glycopeptide antibiotics, including vancomycin and teicoplanin, target this motif by forming hydrogen bonds with the D-Ala-D-Ala dipeptide, which sterically inhibits the transpeptidation and transglycosylation steps of cell wall synthesis (PubMed, PMID: 11084357). The pentaglycine bridge is a specific interpeptide cross-link, most notably found in Staphylococcus aureus, that connects the L-lysine of one peptide stem to the D-alanine of another (PubMed, PMID: 1489457). This bridge is the primary target for the bacteriolytic enzyme lysostaphin, which cleaves the glycine-glycine bonds within the bridge to cause rapid cell wall degradation (PubMed, PMID: 15105404). Because these structures are unique to bacteria and absent in human cells, they represent highly selective targets for antimicrobial therapy. However, the emergence of resistance, such as the modification of D-Ala-D-Ala to D-Ala-D-Lac, poses a significant challenge to the continued efficacy of drugs targeting these sites (PubMed, PMID: 10601204). These targets are primarily relevant in the treatment of severe infections caused by Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE).

Other names

D-Ala-D-Ala terminusPentaglycine bridgePeptidoglycan cross-bridgeLipid II D-Ala-D-Ala

Glycopeptide antibiotics bind to the D-Ala-D-Ala terminus to inhibit transpeptidation and transglycosylation, while enzymes like lysostaphin cleave the pentaglycine bridge to cause bacterial lysis.