The VanA-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 VanA operon, which encodes enzymes and regulatory proteins that alter the bacterial cell wall, making it resistant to vancomycin. The operon is made up of 7 genes which can be divided into regulatory (vanR and vanS), resistance (vanH, vanA and vanX) and accessory genes (vanY and vanZ). 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. 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). A D-Ala-D-Ala dipeptidase, encoded by the vanX gene, hydrolyzes D-Ala-D-Ala dipeptides thus preventing their integration into the peptidoglycan and subsequent peptidoglycan formation in the presence of vancomycin. vanA encodes a D-alanine D-alanine ligase which synthesizes the D-Ala-D-Lac dipeptide that replaces the normal D-Ala-D-Ala in the peptidoglycan precursor, thereby reducing vancomycin's binding affinity. Additionally, 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 while VanZ confers teicoplanin resistance through an unknown mechanism.

Vancomycin resistance pathway (VanA operon) References