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Antimicrobial Agents and Chemotherapy, March 2003, p. 854-862, Vol. 47, No. 3
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.3.854-862.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Quinolone-DNA Interaction: Sequence-Dependent Binding to Single-Stranded DNA Reflects the Interaction within the Gyrase-DNA Complex

Christian G. Noble,^1,2, Faye M. Barnard,^1, and Anthony Maxwell^1,2*

Department of Biochemistry, University of Leicester, Leicester LE1 7RH,¹ Department of Biological Chemistry, John Innes Centre, Norwich Research Park, Colney, Norwich NR4 7UH, United Kingdom²

Received 12 September 2002/ Returned for modification 1 November 2002/ Accepted 9 December 2002

We have investigated the interaction of quinolones with DNA by a number of methods to establish whether a particular binding mode correlates with quinolone potency. The specificities of the quinolone-mediated DNA cleavage reaction of DNA gyrase were compared for a number of quinolones. Two patterns that depended on the potency of the quinolone were identified. Binding to plasmid DNA was examined by measuring the unwinding of pBR322 by quinolones; no correlation with quinolone potency was observed. Quinolone binding to short DNA oligonucleotides was measured by surface plasmon resonance. The quinolones bound to both single- and double-stranded oligonucleotides in an Mg²⁺-dependent manner. Quinolones bound to single-stranded DNA with a higher affinity, and the binding exhibited sequence dependence; binding to double-stranded DNA was sequence independent. The variations in binding in the presence of metal ions showed that Mg²⁺ promoted tighter, more specific binding to single-stranded DNA than softer metal ions (Mn²⁺ and Cd²⁺). Single-stranded DNA binding by quinolones correlated with the in vitro quinolone potency, indicating that this mode of interaction may reflect the interaction of the quinolone with DNA in the context of the gyrase-DNA complex.

Present address: Division of Protein Structure, National Institute for Medical Research, London NW7 1AA, United Kingdom.

Present address: School of Pharmaceutical Sciences, University of Nottingham, Nottingham NG2 2RD, United Kingdom.

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