Moderate-Level Resistance to Glycopeptide LY333328 Mediated by Genes of the vanA and vanB Clusters in Enterococci

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Abstract
Three of five natural plasmids carrying a wild-typevanA gene cluster did not confer LY333328 glycopeptide resistance on Enterococcus faecalis JH2-2 (MIC = 2 μg/ml). The two remaining plasmids conferred resistance to the drug (MIC, 8 μg/ml). The vanB gene cluster did not confer resistance to LY333328, since this antibiotic was not an inducer. Mutations in the vanSB sensor gene that allowed induction by teicoplanin or constitutive expression of thevanB cluster led to LY333328 resistance (MIC, 8 to 16 μg/ml). Overproduction of the VanH, VanA, and VanX proteins ford-alanyl-d-lactate (d-Ala-d-Lac) synthesis andd-Ala-d-Ala hydrolysis was sufficient for resistance to LY333328 (MIC, 16 μg/ml). Mutations in the hostd-Ala:d-Ala ligase contributed to LY333328 resistance in certain VanA- and VanB-type strains, but the MICs of the antibiotic did not exceed 16 μg/ml. Addition ofd-2-hydroxybutyrate in the culture medium of mutants that did not produce the VanH d-lactate dehydrogenase led to incorporation of this d-2-hydroxy acid at the C-terminal ends of the peptidoglycan precursors and to LY333328 resistance (MIC, 64 μg/ml). The vanZ gene of the vanA cluster conferred resistance to LY333328 (MIC, 8 μg/ml) by an unknown mechanism. These data indicate that VanA- and VanB-type enterococci may acquire moderate-level resistance to LY333328 (MIC ≤ 16 μg/ml) in a single step by various mechanisms.