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Antimicrobial Agents and Chemotherapy, January 2003, p. 77-81, Vol. 47, No. 1
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.1.77-81.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Contribution of the 8-Methoxy Group to the Activity of Gatifloxacin against Type II Topoisomerases of Streptococcus pneumoniae

Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd., Shimotsuga, Tochigi 329-0114, Japan

Received 15 April 2002/ Returned for modification 26 June 2002/ Accepted 13 September 2002

The inhibitory activities (50% inhibitory concentrations [IC₅₀s]) of gatifloxacin and other quinolones against both DNA gyrase and topoisomerase IV of the wild-type Streptococcus pneumoniae IID553 were determined. The IC₅₀s of 10 compounds ranged from 4.28 to 582 µg/ml against DNA gyrase and from 1.90 to 35.2 µg/ml against topoisomerase IV. The inhibitory activity against DNA gyrase was more varied than that against topoisomerase IV among fluoroquinolones. The IC₅₀s for DNA gyrase of the 8-methoxy quinolones gatifloxacin and AM-1147 were approximately seven times lower than those of their 8-H counterparts AM-1121 and ciprofloxacin, whereas the IC₅₀s for topoisomerase IV were 1.5 times lower. Moreover, the IC₅₀ ratios (IC₅₀ for DNA gyrase/IC₅₀ for topoisomerase IV) of gatifloxacin, AM-1147, and moxifloxacin, which possess 8-methoxy groups, were almost the same. The 8-methoxy quinolones showed higher antibacterial activity and less mutant selectivity against IID553 than their 8-H counterparts. These results suggest that the 8-methoxy group enhances both target inhibition, especially for DNA gyrase, leading to potent antipneumococcal activity and dual inhibition against both DNA gyrase and topoisomerase IV in the bacterial cell.

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