D-alanine--D-lactate ligase (VanA)

D-alanine--D-lactate ligase is a bacterial enzyme that plays a critical role in mediating high-level resistance to glycopeptide antibiotics, most notably vancomycin and teicoplanin. [1] In susceptible bacteria, D-alanine-D-alanine ligase synthesizes the D-Ala-D-Ala dipeptide required for cell wall cross-linking, which serves as the primary binding site for vancomycin. [2] In resistant strains such as Vancomycin-resistant Enterococci (VRE), the D-alanine--D-lactate ligase catalyzes the synthesis of a D-alanyl-D-lactate depsipeptide instead. [3] This structural modification results in the loss of a key hydrogen bond, reducing vancomycin's binding affinity by nearly 1,000-fold and allowing the bacteria to maintain cell wall integrity during antibiotic treatment. [4] As a therapeutic target, the enzyme is a focal point for the development of adjuvants designed to overcome antibiotic resistance and restore the clinical utility of glycopeptides against multi-drug resistant pathogens. [5] Because this metabolic pathway is unique to prokaryotes, inhibitors of this ligase are expected to have high selectivity and minimal off-target effects in human hosts. [6]

Other names

D-alanyl-D-lactate synthaseVanBVanDVanMD-Ala-D-Lac ligaseDepsipeptide ligase

Inhibition of the enzyme's catalytic site to prevent the formation of D-Ala-D-Lac depsipeptides, thereby restoring the presence of D-Ala-D-Ala termini and re-sensitizing the bacteria to glycopeptide antibiotics.