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Antimicrobial Agents and Chemotherapy, October 2009, p. 4441-4449, Vol. 53, No. 10
0066-4804/09/$08.00+0     doi:10.1128/AAC.00529-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

High-Throughput Screening Identifies Three Inhibitor Classes of the Telomere Resolvase from the Lyme Disease Spirochete {triangledown}

Georgia Lefas and George Chaconas*

Department of Biochemistry and Molecular Biology and Department of Microbiology and Infectious Diseases, University of Calgary, 3330 Hospital Dr. N.W., Calgary, Alberta T2N 4N1, Canada

Received 21 April 2009/ Returned for modification 1 June 2009/ Accepted 6 July 2009

Lyme disease, the most common vector-borne zoonosis in North America, is caused by the spirochetal pathogen Borrelia burgdorferi. The telomere resolvase encoded by this organism (ResT) promotes the formation of covalently closed hairpin ends on the linear DNA molecules of B. burgdorferi through a two-step transesterification. ResT is essential for survival and is therefore an attractive target for the development of highly specific antiborrelial drugs. To identify ResT inhibitors, a novel fluorescence-based high-throughput assay was developed and used to screen a library of 27,520 small-molecule drug-like compounds. Six confirmed inhibitors of ResT, with 50% inhibitory concentrations between 2 and 10 µM, were identified. The inhibitors were characterized further and were grouped into three distinct classes based on their inhibitory features. The high-throughput screening assay developed in this paper, along with the six inhibitory compounds identified, provides a starting point for the future development of novel antiborrelial drugs as well as small-molecule inhibitors that will be helpful for the further dissection of the reaction mechanism.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, 3330 Hospital Drive N.W., Calgary, Alberta T2N 4N1, Canada. Phone: (403) 210-9692. Fax: (403) 270-2772. E-mail: chaconas{at}ucalgary.ca

{triangledown} Published ahead of print on 13 July 2009.

Antimicrobial Agents and Chemotherapy, October 2009, p. 4441-4449, Vol. 53, No. 10
0066-4804/09/$08.00+0     doi:10.1128/AAC.00529-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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