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JAC Advance Access originally published online on February 22, 2007
Journal of Antimicrobial Chemotherapy 2007 59(4):640-645; doi:10.1093/jac/dkl556
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

Compounds with antibacterial activity that enhance DNA cleavage by bacterial DNA topoisomerase I

Bokun Cheng, I-Fen Liu and Yuk-Ching Tse-Dinh*

Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA

Received 13 October 2006; returned 4 December 2006; revised 14 December 2006; accepted 21 December 2006

* Corresponding author. Tel: +1-914-594-4061; Fax: +1-914-594-4058; E-mail: yuk-ching_tse-dinh{at}nymc.edu

Objectives: DNA topoisomerases utilize a covalent complex formed after DNA cleavage as an intermediate in the interconversion of topological forms via DNA cleavage and religation. Many anticancer and antibacterial therapeutic agents are effective because they stabilize or increase the level of the covalent topoisomerase–DNA complex formed by type IIA or type IB topoisomerases. Our goal is to identify small molecules that can enhance DNA cleavage by type IA DNA topoisomerase. Compounds that act in this mechanism against type IA topoisomerase have not been identified previously and could be leads for development of a new class of antibacterial agents.

Methods: High throughput screening was carried out to select small molecules that induce the SOS response of Escherichia coli, overexpressing recombinant Yersinia pestis topoisomerase I. The initial hit compounds were further tested for inhibition of bacterial growth and bacterial topoisomerase I activity.

Results: Three compounds with antibacterial activity that enhance the cleavage activity of bacterial topoisomerase I were identified.

Conclusions: Small molecules that can enhance the DNA cleavage activity of type IA DNA topoisomerase can be identified and may provide leads for development of novel antibacterial compounds.

Keywords: antibiotics , high throughput screening , Y. pestis


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This article has been cited by other articles:


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E. P. Sorokin, B. Cheng, S. Rathi, S. J. Aedo, M. V. Abrenica, and Y.-C. Tse-Dinh
Inhibition of Mg2+ binding and DNA religation by bacterial topoisomerase I via introduction of an additional positive charge into the active site region
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J. H. Sutherland, B. Cheng, I-F. Liu, and Y.-C. Tse-Dinh
SOS Induction by Stabilized Topoisomerase IA Cleavage Complex Occurs via the RecBCD Pathway
J. Bacteriol., May 1, 2008; 190(9): 3399 - 3403.
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B. Cheng, E. P. Sorokin, and Y.-C. Tse-Dinh
Mutation adjacent to the active site tyrosine can enhance DNA cleavage and cell killing by the TOPRIM Gly to Ser mutant of bacterial topoisomerase I
Nucleic Acids Res., February 11, 2008; 36(3): 1017 - 1025.
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