Mechanisms and implications of glycopeptide resistance in enterococci

Glycopeptide resistance is recent in enterococci and its expression is inducible by glycopeptides. Two phenotypes can be distinguished: (a) resistance to high levels of vancomycin and teicoplanin, and (b) resistance to low levels of vancomycin only. There is no cross-resistance between glycopeptides, glycolipodepsipeptides (ramoplanin), and lipopeptides (daptomycin). The determinants conferring low-level resistance are nontransferable and presumably chromosomal. High-level resistance is plasmid-mediated and the plasmids range from 34 to 40 kb, are self-transferable, and encode various resistance combinations. All plasmids share the same glycopeptide resistance determinant, which is distinct from that conferring low-level resistance. Induction of resistance is associated with induction of about a 40 kDa protein. We have determined the sequence of the vanA gene encoding one such resistance protein designated VANA. Amino acid sequence similarity was detected between VANA and D-Ala: D-Ala ligases from Enterobacteriaceae. Complementation analysis in Escherichia coli indicated that VANA possesses D-Ala: D-Ala ligase activity and is therefore related to enzymes that catalyze synthesis of glycopeptide target, i.e., terminal D-Ala-D-Ala of peptidoglycan precursors. The contribution of VANA to synthesis of peptidoglycan in the presence of glycopeptides is unknown: VANA could bind to D-Ala-D-Ala, preventing the binding of the drugs; could modify the target of the drug; and could be a ligase with novel specificity.