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JAC Advance Access published online on September 26, 2006
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkl388
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Received May 15, 2006
Revised August 10, 2006
Accepted September 4, 2006

Brief report

Bactericidal activity and target preference of a piperazinyl-cross-linked ciprofloxacin dimer with Staphylococcus aureus and Escherichia coli

Xilin Zhao 1, Brian Quinn 1, Robert Kerns 2, and Karl Drlica 1 *

1 Public Health Research Institute, 225 Warren Street, Newark, NJ 07103, USA
2 Division of Medicinal and Natural Products Chemistry, The University of Iowa, Iowa City, IA 52242, USA

* To whom correspondence should be addressed.
Karl Drlica, E-mail: drlica{at}phri.org


  Abstract

Background: Previous work showed that piperazinyl-cross-linked ciprofloxacin dimer exhibits good bacteriostatic activity with Streptococcus pneumoniae and Staphylococcus aureus; lethal activity was not measured. Subsequently, the dimer failed to kill Mycobacterium smegmatis but blocked growth. Whether the compound is lethal with non-mycobacterial species is not known.

Methods: Bacteriostatic and bactericidal activities were measured with wild-type cells and topoisomerase mutants of S. aureus and Escherichia coli for ciprofloxacin and a dimer of ciprofloxacin. Spontaneous resistance mutants were selected with S. aureus for both compounds, followed by target identification by nucleotide sequence determination of the quinolone-resistance-determining-region of gyrA (gyrase) and parC (topoisomerase IV).

Results: The dimer was lethal, in some cases exhibiting more activity than ciprofloxacin (particularly with wild-type cells and a parC mutant of S. aureus). Dimerization affected target preference with S. aureus but not with E. coli. Resistance mutations in either gyrA or parC of S. aureus raised the MIC of the dimer, but only a parC mutation raised the MIC of ciprofloxacin. With S. aureus, the dimer selected spontaneous resistant gyrA mutants, whereas ciprofloxacin selected a parC mutant. With E. coli, a gyrA, but not a parC, mutation raised the MIC of both compounds.

Conclusion: The dimer readily killed S. aureus and E. coli, representative Gram-positive and Gram-negative bacteria. In both cases the preferred target was DNA gyrase. The switch in target preference may be responsible for the greater lethality of the dimer seen with S. aureus.

Keywords: fluoroquinolones; gyrase; topoisomerase IV.
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