D-alanyl-D-lactate (D-Ala-D-Lac) (D-Ala-D-Lac)

D-alanyl-D-lactate is a depsipeptide that replaces the standard D-alanyl-D-alanine terminus in the peptidoglycan precursors of certain Gram-positive bacteria, most notably Vancomycin-Resistant Enterococci (VRE) (Bugg et al., 1991, Biochemistry). This modification is a key mechanism of antibiotic resistance, mediated by the VanA, VanB, and VanD operons which encode enzymes that synthesize D-lactate and ligate it to D-alanine (Arthur et al., 1996, Journal of Bacteriology). The substitution of the amide NH group in the native D-Ala-D-Ala with an ester oxygen in D-Ala-D-Lac results in the loss of a critical hydrogen bond required for vancomycin binding, reducing the drug's affinity by approximately 1,000-fold (Courvalin, 2006, Clinical Infectious Diseases). Consequently, D-alanyl-D-lactate serves as the primary molecular determinant of high-level glycopeptide resistance in clinical settings. Therapeutic strategies to overcome this resistance involve the development of lipoglycopeptides, such as oritavancin and telavancin, which are designed to bind to the D-Ala-D-Lac terminus through enhanced hydrophobic interactions and secondary binding sites (Zhanel et al., 2010, Drugs). Understanding the structural biology of D-alanyl-D-lactate is essential for the ongoing development of next-generation antibiotics targeting multi-drug resistant pathogens (PubChem CID 123954).

Other names

D-Ala-D-LacD-alanyl-D-lactic acidPeptidoglycan depsipeptide terminusVancomycin-resistant peptidoglycan precursor

Inhibition of bacterial cell wall synthesis by binding to the peptidoglycan precursor terminus, thereby blocking transglycosylation and transpeptidation.