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Antimicrobial Agents and Chemotherapy, June 2004, p. 2108-2115, Vol. 48, No. 6
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.6.2108-2115.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Ciprofloxacin Dimers Target Gyrase in Streptococcus pneumoniae

Molecular Genetics Group, Department of Basic Medical Sciences-Biochemistry and Immunology, St. George's Hospital Medical School, University of London, London SW17 0RE, United Kingdom,¹ Division of Medicinal and Natural Products Chemistry, The University of Iowa, Iowa City, Iowa 52242²

Received 25 September 2003/ Returned for modification 19 December 2003/ Accepted 21 February 2004

We have examined the antipneumococcal activities of novel quinolone dimers in which ciprofloxacin was tethered to itself or to pipemidic acid by linkage of C-7 piperazinyl rings. Symmetric 2,6-lutidinyl- and trans-butenyl-linked ciprofloxacin dimers (dimers 1 and 2, respectively) and a pipemidic acid-ciprofloxacin dimer (dimer 3) had activities against Streptococcus pneumoniae strain 7785 that were comparable to that of ciprofloxacin, i.e., MICs of 2, 1, and 4 to 8 µg/ml versus an MIC of 1 to 2 µg/ml, respectively. Surprisingly, unlike ciprofloxacin (which targets topoisomerase IV), several lines of evidence revealed that the dimers act through gyrase in S. pneumoniae. First, ciprofloxacin-resistant parC mutants of strain 7785 remained susceptible to dimers 1 to 3, whereas a gyrA mutation conferred a four- to eightfold increase in the dimer MIC but had little effect on ciprofloxacin activity. Second, dimer 1 selected first-step gyrA (S81Y or S81F) mutants (MICs, 8 to 16 µg/ml) that carried wild-type topoisomerase IV parE-parC genes. Third, dimers 1 and 2 promoted comparable DNA cleavage by S. pneumoniae gyrase and topoisomerase IV, whereas ciprofloxacin-mediated cleavage was 10-fold more efficient with topoisomerase IV than with gyrase. Fourth, the GyrA S81F and ParC S79F enzymes were resistant to dimers, confirming that the resistance phenotype is largely silent in parC mutants. Although a dimer molecule could bind very tightly by bridging quinolone binding sites in the enzyme-DNA complex, the greater potency of ciprofloxacin against gyrase and topoisomerase IV suggests that dimers 1 to 3 bind in a monomeric fashion. The bulky C-7 side chain may explain dimer targeting of gyrase and activity against efflux mutants. Tethered quinolones have potential as mechanistic tools and as novel antimicrobial agents.

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