The VanD-type vancomycin resistance pathway enables enterococcal bacteria to resist the action of the glycopeptide antibiotic vancomycin. This pathway involves a series of genes organized in an the VanD operon, which encodes enzymes and regulatory proteins that alter the bacterial cell wall, making it resistant to vancomycin. The operon is made up of 5 genes which can be divided into regulatory (vanR and vanS), resistance (vanH, vanD and vanX) and accessory (vanY). The vanR gene is a response regulator that is part of a two-component regulatory system and activates transcription once phosphorylated by histidine kinase that is encoded by vanS, after detecting vancomycin. vanD gene encodes a D-Ala-D-Lac ligase, synthesizing the D-Ala-D-Lac (D-alanine-D-lactate) dipeptide, replacing the typical D-Ala-D-Ala in the peptidoglycan precursor, which has reduced affinity for vancomycin and is added to UDP-MurNAc-tripeptide. vanX encodes a D,D-dipeptidase that hydrolyzes D-Ala-D-Ala dipeptides, ensuring that only D-Ala-D-Lac is available for incorporation into the peptidoglycan, and subsequent peptidoglycan formation even in the presence of vancomycin. The vanH gene encodes an e D-lactate dehydrogenase, which converts pyruvate to D-lactate, a precursor for the altered peptidoglycan precursor (to counteract the effects of vancomycin, which targets the peptidoglycan by binding to D-alanine-D-alanine terminus of the peptide chains, inhibiting cell wall synthesis). Lastly, the accessory gene vanY, encodes a D,D-carboxypeptidase that, ensures that only D-Ala-D-Lac is used in cell wall synthesis by eliminating the terminal D-alanine residue from peptidoglycan precursors

Vancomycin resistance pathway (VanD operon) References