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JAC Advance Access published online on July 26, 2006
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkl297
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Received March 10, 2006
Revised June 28, 2006
Accepted July 2, 2006

Original article

Role of type II topoisomerase mutations and AcrAB efflux pump in fluoroquinolone-resistant clinical isolates of Proteus mirabilis

Ryoichi Saito 1 *, Kenya Sato 2, Wakako Kumita 2, Natsuko Inami 2, Hiroyuki Nishiyama 2, Noboru Okamura 2, Kyoji Moriya 3, and Kazuhiko Koike 3

1 Department of Infection Control and Prevention, The University of Tokyo Hospital, Bunkyo-ku, Tokyo 113-8655, Japan; Department of Microbiology and Immunology, Graduate School of Allied Health Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan
2 Department of Microbiology and Immunology, Graduate School of Allied Health Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan
3 Department of Infection Control and Prevention, The University of Tokyo Hospital, Bunkyo-ku, Tokyo 113-8655, Japan

* To whom correspondence should be addressed.
Ryoichi Saito, E-mail: saito-lab{at}h.u-tokyo.ac.jp


  Abstract

Objectives: We conducted a study to determine the role played by amino acid mutations in DNA gyrase and topoisomerase IV, and the AcrAB efflux pump in resistance to fluoroquinolones in clinical isolates of Proteus mirabilis.

Methods: Nine clinical isolates of P. mirabilis containing eight fluoroquinolone-resistant isolates and one fluoroquinolone-susceptible isolate as the causative pathogen were collected from different patients with urinary tract infections. Fluoroquinolone resistance was characterized by PCR and DNA sequencing. The role of the AcrAB efflux pump was investigated by semi-quantifying the transcriptional expression of the acrB gene.

Results: Double mutations were found in GyrA, at S83I and E87K, and single mutations in GyrB (S464F) and ParC (S80I) in four isolates with ciprofloxacin MICs of 16 to >128 mg/L. In three isolates (ciprofloxacin MICs of >128 mg/L), the level of acrB expression was 2.1- to 3.2-fold higher than that in the wild-type control strain (ciprofloxacin MIC of ≤0.12 mg/L) and these isolates also had increased MICs of minocycline (>64 versus 8-16 mg/L) and chloramphenicol (>256 versus 4-8 mg/L) compared with the five other fluoroquinolone-resistant isolates.

Conclusion: Our findings demonstrate that two mechanisms--mutations in GyrA (at S83I and E87K), GyrB and ParC, and overproduction of the AcrAB efflux pump--might synergistically contribute to a highest level of resistance to fluoroquinolones in clinical isolates of P. mirabilis.

Keywords: P. mirabilis; DNA gyrase; topoisomerase IV.
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