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

Richter, SN; Giaretta, G; Comuzzi, V; Leo, E; Mitchenall, LA; Fisher, LM; Maxwell, A; Palumbo, M (2007) Hot-spot consensus of fluoroquinolone-mediated DNA cleavage by gram-negative and gram-positive type II DNA topoisomerases. NUCLEIC ACIDS RESEARCH, 35 (18). 6075 - 6085. ISSN 0305-1048 https://doi.org/10.1093/nar/gkm653
SGUL Authors: Fisher, Larry Mark

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Abstract

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.

Item Type: Article
Additional Information: Copyright: 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.
Keywords: Anti-Bacterial Agents, Base Sequence, Ciprofloxacin, Consensus Sequence, DNA, DNA Gyrase, DNA Topoisomerase IV, Escherichia coli, Fluoroquinolones, Guanine, Naphthyridines, Streptococcus pneumoniae, Substrate Specificity, Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, BIOCHEMISTRY & MOLECULAR BIOLOGY, ESCHERICHIA-COLI, STREPTOCOCCUS-PNEUMONIAE, DOUBLE HELIX, GYRASE, IV, SITE, PURIFICATION, QUINOLONES, MECHANISM, SEQUENCES, Developmental Biology, 05 Environmental Sciences, 06 Biological Sciences, 08 Information And Computing Sciences
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cell Sciences (INCCCS)
Journal or Publication Title: NUCLEIC ACIDS RESEARCH
ISSN: 0305-1048
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Dates:
DateEvent
1 September 2007Published
Web of Science ID: WOS:000250683600017
URI: http://openaccess.sgul.ac.uk/id/eprint/107082
Publisher's version: https://doi.org/10.1093/nar/gkm653

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