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Antimicrobial Agents and Chemotherapy, February 2002, p. 413-419, Vol. 46, No. 2
0066-4804/01/$04.00+0     DOI: 10.1128/AAC.46.2.413-419.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Cleavable-Complex Formation by Wild-Type and Quinolone-Resistant Streptococcus pneumoniae Type II Topoisomerases Mediated by Gemifloxacin and Other Fluoroquinolones

Genoveva Yague,,{dagger} Julia E. Morris, Xiao-Su Pan, Katherine A. Gould, and L. Mark Fisher*

Molecular Genetics Group, Department of Biochemistry and Immunology, St. George's Hospital Medical School, University of London, London SW17 0RE, United Kingdom

Received 20 August 2001/ Returned for modification 8 October 2001/ Accepted 6 November 2001

Gemifloxacin is a recently developed fluoroquinolone with potent activity against Streptococcus pneumoniae. We show that the drug is more active than moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin against S. pneumoniae strain 7785 (MICs, 0.03 to 0.06 µg/ml versus 0.25, 0.25, 1, and 1 to 2 µg/ml, respectively) and against isogenic quinolone-resistant gyrA-parC mutants (MICs, 0.5 to 1 µg/ml versus 2 to 4, 2 to 4, 16 to 32, and 64 µg/ml, respectively). Gemifloxacin was also the most potent agent against purified S. pneumoniae DNA gyrase and topoisomerase IV in both catalytic inhibition and DNA cleavage assays. The drug concentrations that inhibited DNA supercoiling or DNA decatenation by 50% (IC50s) were 5 to 10 and 2.5 to 5.0 µM, respectively. Ciprofloxacin and levofloxacin were some four- to eightfold less active against either enzyme; moxifloxacin and gatifloxacin showed intermediate activities. In assays of drug-mediated DNA cleavage by gyrase and topoisomerase IV, the same order of potency was seen: gemifloxacin > moxifloxacin > gatifloxacin > levofloxacin {approx} ciprofloxacin. For gemifloxacin, the drug concentrations that caused 25% linearization of the input DNA by gyrase and topoisomerase IV were 2.5 and 0.1 to 0.3 µM, respectively; these values were 4-fold and 8- to 25-fold lower than those for moxifloxacin, respectively. Each drug induced DNA cleavage by gyrase at the same spectrum of sites but with different patterns of intensity. Finally, for enzymes reconstituted with quinolone-resistant GyrA S81F or ParC S79F subunits, although cleavable-complex formation was reduced by at least 8- to 16-fold for all the quinolones tested, gemifloxacin was the most effective; e.g., it was 4- to 16-fold more active than the other drugs against toposiomerase IV with the ParC S79F mutation. It appears that the greater potency of gemifloxacin against both wild-type and quinolone-resistant S. pneumoniae strains arises from enhanced stabilization of gyrase and topoisomerase IV complexes on DNA.

* Corresponding author. Mailing address: Molecular Genetics Group, Department of Biochemistry and Immunology, St. George's Hospital Medical School, University of London, Cranmer Terrace, London SW17 0RE, United Kingdom. Phone: 44 208 725 5782. Fax: 44 208 725 2992. E-mail: lfisher{at}sghms.ac.uk.

{dagger} Present address: Departamento de Genetica y Microbiologia, Facultad de Medicina, Universidad de Murcia, Campus de Espinardo, 30100 Murcia, Spain

Antimicrobial Agents and Chemotherapy, February 2002, p. 413-419, Vol. 46, No. 2
0066-4804/01/$04.00+0     DOI: 10.1128/AAC.46.2.413-419.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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