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Antimicrobial Agents and Chemotherapy, October 2007, p. 3688-3698, Vol. 51, No. 10
0066-4804/07/$08.00+0     doi:10.1128/AAC.00392-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Discovery of Novel DNA Gyrase Inhibitors by High-Throughput Virtual Screening{triangledown}

David A. Ostrov,1* José A. Hernández Prada,1 Patrick E. Corsino,2 Kathryn A. Finton,2 Nhan Le,2 and Thomas C. Rowe2*

Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, 1600 SW Archer Road, Gainesville, Florida 32610,1 Department of Pharmacology and Therapeutics, University of Florida College of Medicine, 1600 SW Archer Road, Gainesville, Florida 32610-02672

Received 22 March 2007/ Returned for modification 21 May 2007/ Accepted 27 July 2007

The bacterial type II topoisomerases DNA gyrase and topoisomerase IV are validated targets for clinically useful quinolone antimicrobial drugs. A significant limitation to widely utilized quinolone inhibitors is the emergence of drug-resistant bacteria due to an altered DNA gyrase. To address this problem, we have used structure-based molecular docking to identify novel drug-like small molecules that target sites distinct from those targeted by quinolone inhibitors. A chemical ligand database containing approximately 140,000 small molecules (molecular weight, <500) was molecularly docked onto two sites of Escherichia coli DNA gyrase targeting (i) a previously unexplored structural pocket formed at the dimer interface of subunit A and (ii) a small region of the ATP binding pocket on subunit B overlapping the site targeted by coumarin and cyclothialidine drugs. This approach identified several small-molecule compounds that inhibited the DNA supercoiling activity of purified E. coli DNA gyrase. These compounds are structurally unrelated to previously identified gyrase inhibitors and represent potential scaffolds for the optimization of novel antibacterial agents that act on fluoroquinolone-resistant strains.

* Corresponding author. Mailing address for David A. Ostrov: Department of Pathology, Immunology and Laboratory Medicine, University of Florida, College of Medicine, Gainesville, FL 32610. Phone: (352) 273-8166. Fax: (352) 273-8285. E-mail: ostroda{at}pathology.ufl.edu. Mailing address for Thomas C. Rowe: Department of Pharmacology and Therapeutics, P.O. Box 100267, Gainesville, FL 32610. Phone: (352) 392 3530. Fax: (352) 392-9696. E-mail: tomrowe{at}ufl.edu

{triangledown} Published ahead of print on 6 August 2007.

Antimicrobial Agents and Chemotherapy, October 2007, p. 3688-3698, Vol. 51, No. 10
0066-4804/07/$08.00+0     doi:10.1128/AAC.00392-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Tse-Dinh, Y.-C. (2009). Bacterial topoisomerase I as a target for discovery of antibacterial compounds. Nucleic Acids Res 37: 731-737 [Abstract] [Full Text]  


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