Peptidoglycan D-alanyl-D-alanine terminus of lipid II precursors (D-Ala-D-Ala)

The D-alanyl-D-alanine (D-Ala-D-Ala) terminus of lipid II precursors is a critical structural motif in the biosynthesis of the bacterial cell wall, specifically in Gram-positive bacteria [1]. Lipid II is the final membrane-associated intermediate that carries the peptidoglycan building blocks across the cytoplasmic membrane [2]. The D-Ala-D-Ala dipeptide at the end of the pentapeptide chain serves as the substrate for transpeptidase enzymes (penicillin-binding proteins) which catalyze the cross-linking of peptidoglycan layers, providing mechanical strength to the cell wall [3]. This terminus is the primary molecular target for glycopeptide antibiotics, such as vancomycin [1]. By binding with high affinity to the D-Ala-D-Ala motif via hydrogen bonding, these drugs sterically inhibit the enzymatic incorporation of the precursor into the growing peptidoglycan polymer, leading to cell wall weakening and osmotic lysis [4]. Resistance often arises through the modification of this target to D-alanyl-D-lactate (D-Ala-D-Lac), which significantly reduces antibiotic binding affinity [5]. Sources: [1] StatPearls (https://www.ncbi.nlm.nih.gov/books/NBK459363/); [2] Nature Reviews Microbiology (https://www.nature.com/articles/nrmicro2020); [3] UniProt (https://www.uniprot.org/locations/SL-0219); [4] JBC (https://www.jbc.org/article/S0021-9258(20)31840-7/fulltext); [5] CDC (https://www.cdc.gov/hai/organisms/vre/vre.html); [6] Mayo Clinic (https://www.mayoclinic.org/drugs-supplements/vancomycin-intravenous-route/side-effects/drg-20068893).

Other names

D-Ala-D-Ala terminusLipid II pentapeptide terminusD-alanyl-D-alanine dipeptidePeptidoglycan precursor C-terminus

Binding to the D-Ala-D-Ala terminus of Lipid II, sterically hindering the transglycosylation and transpeptidation steps of peptidoglycan synthesis [1, 4].