Lipid II terminal D-alanyl-D-alanine (Lipid II D-Ala-D-Ala)

Lipid II terminal D-Ala-D-Ala is a specific dipeptide motif located at the C-terminus of the pentapeptide chain of Lipid II, an essential precursor in bacterial peptidoglycan biosynthesis [1, 4]. This motif serves as the primary molecular target for glycopeptide antibiotics, such as vancomycin and teicoplanin, which bind to it with high affinity through a network of five hydrogen bonds [1, 6]. By sequestering the Lipid II substrate, these antibiotics sterically hinder the enzymes responsible for transglycosylation and transpeptidation, effectively halting the assembly of the bacterial cell wall [2, 12]. This disruption leads to cell wall instability and eventual osmotic lysis of the bacterium [2, 8]. The target is highly conserved among Gram-positive bacteria, making it critical for treating infections caused by pathogens like methicillin-resistant Staphylococcus aureus (MRSA) [1, 10]. However, clinical resistance can occur through the modification of this terminus to D-alanyl-D-lactate (D-Ala-D-Lac), which significantly reduces the binding affinity of most glycopeptides [3, 9]. Newer lipoglycopeptides like oritavancin have been developed to overcome this resistance by utilizing additional binding sites on the Lipid II molecule [2, 12].

Other names

D-alanyl-D-alanine terminus of Lipid IILipid II pentapeptide terminusD-Ala-D-Ala moiety of Lipid IILipid II D-Ala-D-Ala

Inhibition of cell wall synthesis by binding to the D-Ala-D-Ala terminus of Lipid II, sequestering the substrate and sterically hindering transglycosylation and transpeptidation.