D-Alanyl-D-Lactate and D-Alanyl-D-Serine modified peptidoglycan termini (D-Ala-D-Lac/D-Ala-D-Ser)

D-Ala-D-Lac and D-Ala-D-Ser modified peptidoglycan termini are altered structural components of the bacterial cell wall precursor, Lipid II, primarily found in glycopeptide-resistant bacteria such as Vancomycin-resistant Enterococci (VRE) (Courvalin, 2006). In susceptible bacteria, glycopeptides bind to the standard D-Ala-D-Ala terminus to inhibit cell wall synthesis; however, the substitution of the terminal D-alanine with D-lactate or D-serine significantly reduces this binding affinity through the loss of critical hydrogen bonds or steric hindrance (Bugg et al., 1991). These modified termini serve as the primary mechanism of resistance against first-generation glycopeptides like vancomycin (Walsh et al., 1996). Consequently, they have become the focus for the development of second-generation lipoglycopeptides, such as oritavancin and telavancin, which possess additional binding mechanisms to overcome these modifications (Blaskovich et al., 2018). Targeting these structures is essential for treating severe infections caused by multidrug-resistant Gram-positive pathogens (StatPearls, 2023).

Other names

Modified peptidoglycan precursorsVancomycin-resistant peptidoglycan terminiD-Ala-D-LacD-Ala-D-SerPeptidoglycan pentapeptide/pentadepsipeptideLipid II modified termini

Inhibition of peptidoglycan polymerization (transglycosylation) and cross-linking (transpeptidation) by binding to the C-terminal D-Ala-D-Lac or D-Ala-D-Ser of the peptidoglycan precursor, thereby blocking the access of penicillin-binding proteins (PBPs).