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J Med Microbiol 55 (2006), 729-736; DOI: 10.1099/jmm.0.46303-0
© 2006 Society for General Microbiology
ISSN 1473-5644

Combination of known and unknown mechanisms confers high-level resistance to fluoroquinolones in Enterococcus faecium

Yoshihiro Oyamada1, Hideaki Ito1, Kouichi Fujimoto1, Reiko Asada1, Toshiyuki Niga1, Ryoichi Okamoto2, Matsuhisa Inoue2 and Jun-ichi Yamagishi1

1 Pharmacology and Microbiology Research Laboratories, Dainippon Pharmaceutical Co. Ltd, Enoki 33-94, Suita, Osaka 564-0053, Japan

2 Department of Microbiology, School of Medicine and Environmental Infectious Disease, Graduate School of Medical Sciences, Kitasato University, Kanagawa, Japan

Correspondence
Hideaki Ito
hideaki-ito{at}ds-pharma.co.jp

Received 23 August 2005
Accepted 31 January 2006

In order to elucidate the mechanisms of fluoroquinolone resistance in Enterococcus faecium, spontaneous mutants isolated from Ent. faecium ATCC 19434 by stepwise selection with sparfloxacin (SPX) or norfloxacin (NOR) and 13 clinical isolates of Ent. faecium were characterized by analysing quinolone-resistance-determining regions (QRDRs) of the gyrA, gyrB, parC and parE genes and examining changes in MICs of SPX and NOR in the presence of efflux pump inhibitors. The SPX-selected first-step mutant had a point mutation only in gyrA, and the mutants QR7-18 and QR7-39, and clinical isolates that had point mutations in parC, showed NOR resistance. These results indicate that the primary targets of SPX and NOR are DNA gyrase and topoisomerase IV, respectively, and therefore that the primary target of fluoroquinolones in Ent. faecium differs depending on the structure of the compound used. The characterization of the spontaneous mutants and the clinical isolates demonstrates that in addition to the previously reported alterations in GyrA and ParC, an alteration in GyrB, a NorA-like pump, an unknown efflux pump, which excretes both SPX and NOR from bacterial cells, and probably other unknown mechanism(s) all contribute to fluoroquinolone resistance in Ent. faecium.

Abbreviations: CCCP, carbonyl cyanide 3-chlorophenylhydrazone; CIP, ciprofloxacin; EtBr, ethidium bromide; MDR, multidrug resistance efflux pump; NOR, norfloxacin; QRDR, quinolone-resistance-determining region; SPX, sparfloxacin.




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Role of a qnr-Like Gene in the Intrinsic Resistance of Enterococcus faecalis to Fluoroquinolones
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Y. Oyamada, H. Ito, M. Inoue, and J.-i. Yamagishi
Topoisomerase mutations and efflux are associated with fluoroquinolone resistance in Enterococcus faecalis.
J. Med. Microbiol., October 1, 2006; 55(Pt 10): 1395 - 1401.
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