D-alanyl-D-lactate peptidoglycan precursor (D-Ala-D-Lac PG precursor)

D-alanyl-D-lactate peptidoglycan precursors are modified structural components of the bacterial cell wall that mediate high-level resistance to glycopeptide antibiotics, most notably vancomycin (Song et al., 2022; Deghorain et al., 2007). In resistant organisms like VanA-type Enterococcus faecium (VRE), the terminal D-alanyl-D-alanine (D-Ala-D-Ala) of the peptidoglycan pentapeptide is replaced with the depsipeptide D-alanyl-D-lactate (D-Ala-D-Lac) (EBI, 2023; ASM, 2018). This modification eliminates a crucial hydrogen bond required for vancomycin binding, leading to a 1,000-fold reduction in antibiotic affinity and allowing cell wall synthesis to continue in the presence of the drug (NIH, 1997; OUP, 2011). These precursors are synthesized through the coordinated action of enzymes such as VanH (a dehydrogenase) and VanA/VanB (ligases) and are subsequently incorporated into the peptidoglycan layer (PNAS, 2000; ASM, 2011). While traditional glycopeptides are ineffective against these modified targets, newer lipoglycopeptides like oritavancin have been engineered to bind D-Ala-D-Lac or utilize alternative mechanisms, such as membrane disruption, to overcome resistance (OUP, 2014; NIH, 2015). Consequently, these precursors represent a significant therapeutic challenge and a key target for overcoming multidrug-resistant Gram-positive infections.

Other names

D-alanyl-D-lactate depsipeptideD-Ala-D-Lac terminiModified peptidoglycan precursorVanA-type peptidoglycan precursorVanB-type peptidoglycan precursorVanD-type peptidoglycan precursor

Inhibition of bacterial cell wall synthesis by binding to peptidoglycan precursors, thereby blocking the transglycosylation and transpeptidation steps of peptidoglycan polymerization.