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Antimicrobial Agents and Chemotherapy, June 2002, p. 1800-1804, Vol. 46, No. 6
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.6.1800-1804.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Inhibitory Activities of Quinolones against DNA Gyrase and Topoisomerase IV of Enterococcus faecalis

Yoshikuni Onodera,* Jun Okuda, Mayumi Tanaka, and Kenichi Sato

New Product Research Laboratories I, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan

Received 10 May 2001/ Returned for modification 2 August 2001/ Accepted 7 March 2002

We have cloned the DNA gyrase and topoisomerase IV genes of Enterococcus faecalis to examine the actions of quinolones against E. faecalis genetically and enzymatically. We first generated levofloxacin-resistant mutants of E. faecalis by stepwise selection with increasing drug concentrations and analyzed the quinolone resistance-determining regions of gyrA and parC from the resistant mutants. Isogenic mutants with low-level resistance contained a mutation in gyrA, whereas those with higher levels of resistance had mutations in both gyrA and parC. These results suggested that gyrA is the primary target for levofloxacin in E. faecalis. We then purified the recombinant DNA gyrase and topoisomerase IV enzymes of E. faecalis and measured the in vitro inhibitory activities of quinolones against these enzymes. The 50% inhibitory concentrations (IC50s) of levofloxacin, ciprofloxacin, sparfloxacin, tosufloxacin, and gatifloxacin for DNA gyrase were found to be higher than those for topoisomerase IV. In conflict with the genetic data, these results indicated that topoisomerase IV would be the primary target for quinolones in E. faecalis. Among the quinolones tested, the IC50 of sitafloxacin (DU-6859a), which shows the greatest potency against enterococci, for DNA gyrase was almost equal to that for topoisomerase IV; its IC50s were the lowest among those of all the quinolones tested. These results indicated that other factors can modulate the effect of target affinity to determine the bacterial killing pathway, but the highest inhibitory actions against both enzymes correlated with good antienterococcal activities.

* 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: onode90j{at}daiichipharm.co.jp.

Antimicrobial Agents and Chemotherapy, June 2002, p. 1800-1804, Vol. 46, No. 6
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.6.1800-1804.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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