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Nucleic Acids Research Advance Access published online on August 30, 2007
Nucleic Acids Research, doi:10.1093/nar/gkm653
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© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Nucleic Acid Enzymes

Hot-spot consensus of fluoroquinolone-mediated DNA cleavage by Gram-negative and Gram-positive type II DNA topoisomerases

Sara N. Richter1,2, Giulia Giaretta1, Valentina Comuzzi1, Elisabetta Leo1,3, Lesley A. Mitchenall4, L. Mark Fisher3, Anthony Maxwell4 and Manlio Palumbo1,*

1Department of Pharmaceutical Sciences, 2Department of Histology, Microbiology and Medical Biotechnologies, University of Padova, 35131 Padova, Italy, 3Molecular Genetics Group, Molecular and Metabolic Signalling Centre, Division of Basic Medical Sciences, St. George's, University of London, London SW17 0RE and 4Department of Biological Chemistry, John Innes Centre, Norwich Research Park, Colney, Norwich NR4 7UH, UK

*To whom correspondence should be addressed. Tel: +39049 827 5699; Fax: +39049 827 5366; Email: manlio.palumbo{at}unipd.it

Received June 16, 2007. Revised July 29, 2007. Accepted August 7, 2007.

Bacterial DNA gyrase and topoisomerase IV are selective targets of fluoroquinolones. Topoisomerase IV versus gyrase and Gram-positive versus Gram-negative behavior was studied based on the different recognition of DNA sequences by topoisomerase–quinolone complexes. A careful statistical analysis of preferred bases was performed on a large number (>400) of cleavage sites. We found discrete preferred sequences that were similar when using different enzymes (i.e. gyrase and topoisomerase IV) from the same bacterial source, but in part diverse when employing enzymes from different origins (i.e. Escherichia coli and Streptococcus pneumoniae). Subsequent analysis on the wild-type and mutated consensus sequences showed that: (i) Gn/Cn-rich sequences at and around the cleavage site are hot spots for quinolone-mediated strand breaks, especially for E. coli topoisomerases: we elucidated positions required for quinolone and enzyme recognition; (ii) for S. pneumoniae enzymes only, A and T at positions –2 and +6 are discriminating cleavage determinants; (iii) symmetry of the target sequence is a key trait to promote cleavage and (iv) the consensus sequence adopts a heteronomous A/B conformation, which may trigger DNA processing by the enzyme–drug complex.


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