Terminal D-alanyl–D-alanine dipeptide of Lipid II (D-Ala–D-Ala (no widely used standard abbreviation specifically for the terminal dipeptide in Lipid II))

The terminal D-alanyl–D-alanine dipeptide of Lipid II is a structural motif that forms the C-terminal end of the pentapeptide stem in the central peptidoglycan precursor, Lipid II, essential for bacterial cell wall synthesis[3][5]. This dipeptide is highly solvent-accessible and flexible, projecting from the Lipid II molecule at the membrane–water interface, and serves as the classical binding site for glycopeptide antibiotics such as vancomycin[1][5][8]. The interaction between vancomycin and the D-Ala–D-Ala terminus sterically prevents peptidoglycan cross-linking enzymes (e.g., penicillin-binding proteins) from accessing Lipid II, thus blocking cell wall biosynthesis and leading to bacterial cell death[5][8]. Resistance arises when bacteria alter this terminus, for example by replacing D-Ala–D-Ala with D-Ala–D-Lac, which reduces antibiotic binding affinity by several orders of magnitude[7][8]. This motif is specific to bacteria and does not occur in human cells, making it a prime target for antibiotic action.

Other names

D-alanyl–D-alanine terminus of Lipid IID-Ala–D-Ala terminusLipid II terminal dipeptide

Direct binding of glycopeptide antibiotics to the D-Ala–D-Ala dipeptide terminus blocks transglycosylation and transpeptidation, inhibiting cell wall biosynthesis and leading to bacterial cell death[3][5][8].