The synthesis of peptidoglycan in the production of bacterial cell walls requires several steps. In the cytoplasm, a racemase converts l-alanine to d-alanine (d-Ala), and then 2 molecules of d-Ala are joined by a ligase, creating the dipeptide d-Ala-d-Ala, which is then added to uracil diphosphate-N-acetylmuramyl-tripeptide to form uracil diphosphate-N-acetylmuramyl-pentapeptide. Uracil diphosphate-N-acetylmuramyl-pentapeptide is bound to the undecaprenol lipid carrier, which, after the addition of GlcNAc from uracil diphosphate-GlcNAc, allows translocation of the precursors to the outer surface of the cytoplasmic membrane. N-acetylmuramyl-pentapeptide is then incorporated into nascent peptidoglycan by transglycosylation and allows the formation of cross-bridges by transpeptidation. Vancomycin binds with high affinity to the d-Ala-d-Ala C-terminus of the pentapeptide, thus blocking the addition of late precursors by transglycosylation to the nascent peptidoglycan chain and preventing subsequent cross-linking by transpeptidation. Vancomycin does not penetrate into the cytoplasm; therefore, interaction with its target can take place only after translocation of the precursors to the outer surface of the membrane.
Because vancomycin does not interact with cell wall biosynthetic enzymes but forms complexes with peptidoglycan precursors, its activity is not determined by the affinity for a target enzyme but by the substrate specificity of the enzymes that determine the structure of peptidoglycan precursors. Resistance to vancomycin is due to the presence of OPERONS that encode enzymes for synthesis of low-affinity precursors, in which the C-terminal d-Ala residue is replaced by d-lactate (d-Lac) or d-serine (d-Ser), thus modifying the vancomyin-binding target; and for elimination of the high-affinity precursors that are normally produced by the host, thus removing the vancomycin-binding target.
Six types of vancomycin resistance have been characterized on both a phenotypic and a genotypic basis in enterococci. VanA, VanB, VanD, VanE, and VanG correspond to acquired resistance; VanC is an intrinsic property of E. gallinarum and E. casseliflavus-E. flavescens. Classification of glycopeptide resistance is currently based on the primary sequence of the structural genes.
Here is a list of vancomycin resistance operons types