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Antimicrobial Agents and Chemotherapy, August 2001, p. 2263-2268, Vol. 45, No. 8
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.8.2263-2268.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Type II Topoisomerase Mutations in Fluoroquinolone-Resistant Clinical Strains of Pseudomonas aeruginosa Isolated in 1998 and 1999: Role of Target Enzyme in Mechanism of Fluoroquinolone Resistance

Takaaki Akasaka,1,* Mayumi Tanaka,1 Akihito Yamaguchi,2 and Kenichi Sato1

New Product Research Laboratories I, Daiichi Pharmaceutical Co., Ltd., Edogawa-ku, Tokyo 134-8630,1 and Department of Cell Membrane Biology, Institute of Scientific and Industrial Research, Osaka University, Ibaraki-shi, Osaka 567-0047,2 Japan

Received 27 December 2000/Returned for modification 12 March 2001/Accepted 8 May 2001

The major mechanism of resistance to fluoroquinolones for Pseudomonas aeruginosa is the modification of type II topoisomerases (DNA gyrase and topoisomerase IV). We examined the mutations in quinolone-resistance-determining regions (QRDR) of gyrA, gyrB, parC, and parE genes of recent clinical isolates. There were 150 isolates with reduced susceptibilities to levofloxacin and 127 with reduced susceptibilities to ciprofloxacin among 513 isolates collected during 1998 and 1999 in Japan. Sequencing results predicted replacement of an amino acid in the QRDR of DNA gyrase (GyrA or GyrB) for 124 of the 150 strains (82.7%); among these, 89 isolates possessed mutations in parC or parE which lead to amino acid changes. Substitutions of both Ile for Thr-83 in GyrA and Leu for Ser-87 in ParC were the principal changes, being detected in 48 strains. These replacements were obviously associated with reduced susceptibilities to levofloxacin, ciprofloxacin, and sparfloxacin; however, sitafloxacin showed high activity against isolates with these replacements. We purified GyrA (The-83 to Ile) and ParC (Ser-87 to Leu) by site-directed mutagenesis and compared the inhibitory activities of the fluoroquinolones. Sitafloxacin showed the most potent inhibitory activities against both altered topoisomerases among the fluoroquinolones tested. These results indicated that, compared with other available quinolones, sitafloxacin maintained higher activity against recent clinical isolates with multiple mutations in gyrA and parC, which can be explained by the high inhibitory activities of sitafloxacin against both mutated enzymes.

* Corresponding author. Mailing address: New Product Research Laboratories I, Daiichi Pharmaceutical Co., Ltd., 16-13, Kitakasai 1-Chome, Edogawa-ku, Tokyo 134-8630, Japan. Phone: 81-3-3680-0151. Fax: 81-3-5696-4264. E-mail: akasa94k{at}daiichipharm.co.jp.

Antimicrobial Agents and Chemotherapy, August 2001, p. 2263-2268, Vol. 45, No. 8
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.8.2263-2268.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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