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Antimicrobial Agents and Chemotherapy, July 2009, p. 2998-3002, Vol. 53, No. 7
0066-4804/09/$08.00+0     doi:10.1128/AAC.00048-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Pharmacological Exploitation of an Off-Target Antibacterial Effect of the Cyclooxygenase-2 Inhibitor Celecoxib against Francisella tularensis{triangledown}

Hao-Chieh Chiu,1 Jian Yang,1 Shilpa Soni,2,3 Samuel K. Kulp,1 John S. Gunn,2,3,4 Larry S. Schlesinger,2,3,4 and Ching-Shih Chen1*

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy,1 Center for Microbial Interface Biology,2 Department of Molecular Virology, Immunology and Medical Genetics,3 Division of Infectious Diseases, Department of Internal Medicine, The Ohio State University, Columbus, Ohio 432104

Received 13 January 2009/ Returned for modification 14 March 2009/ Accepted 19 April 2009

Francisella tularensis, a bacterium which causes tularemia in humans, is classified as a CDC category A bioterrorism agent. In this study, we demonstrate that celecoxib, an anti-inflammatory cyclooxygenase-2 inhibitor in clinical use, exhibits activity against a type A strain of F. tularensis (Schu S4), the live vaccine strain of F. tularensis (a type B strain), and F. novicida ("F. tularensis subsp. novicida") directly in growth medium. This bacterial killing, however, was not noted with rofecoxib, despite its higher potency than that of celecoxib in inhibiting cyclooxygenase-2. The unique ability of celecoxib to inhibit the proliferation of F. tularensis could be pharmacologically exploited to develop novel anti-Francisella therapeutic agents, of which the proof of principle is demonstrated by compound 20, a celecoxib derivative identified through the screening of a celecoxib-based focused compound library. Compound 20 inhibited the intracellular proliferation of Francisella in macrophages without causing appreciable toxicity to these host cells. Together, these data support the translational potential of compound 20 for the further development of novel, potent anti-Francisella agents.

* Corresponding author. Mailing address: Division of Medicinal Chemistry, College of Pharmacy, 336 L. M. Parks Hall, 500 West 12th Avenue, Columbus, OH 43210. Phone: (614) 688-4008. Fax: (614) 688-8556. E-mail: chen.844{at}osu.edu

{triangledown} Published ahead of print on 27 April 2009.

Antimicrobial Agents and Chemotherapy, July 2009, p. 2998-3002, Vol. 53, No. 7
0066-4804/09/$08.00+0     doi:10.1128/AAC.00048-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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