22 High-Throughput Screening of a Drug Library for Leishmania Major

Wednesday, November 4, 2009
Ballroom A+B (Camino Real Hotel)
Miguel A. Vasquez , Biological Sciences, University of Texas at El Paso, El Paso, TX
Stephen M. Beverley , School of Medicine, Washington University, St. Louis, MO
Carolina Lema , Biological Sciences, University of Texas at El Paso, El Paso, TX
Jonathan Dimmock , Department of Chemistry, University of Saskatchewan, Saskatoon, SK, Canada
Rosa A. Maldonado , Biological Sciences, University of Texas at El Paso, El Paso, TX
The protozoan trypanosome Leishmania major is an obligate intracellular parasite that is the causative agent for cutaneous leishmaniasis.  This disease is endemic is many regions such as Asia, Africa, South America, Latin America, and with the constant deployment of U.S. troops to endemic areas it has now become a major concern for the U.S. as well.  Therapeutic treatment for this disease is very limited with only antimony-containing compounds and fungicides being used as the primary treatment.  However, these drugs can be toxic to patients and there has been a rise in frequent treatment failures as a result of drug resistance.  This has led to a higher demand for the availability of newly synthesized therapeutic drugs.  High-throughput drug screening provides a starting point for drug design and for understanding the interaction of a compound with its target site.  In this study, this method is being used to perform experiments on promastigote forms of L. major (Freidlin V1) and LLC-MK2 mammalian cells using the Dimmock library.  Viability of L. major is rapidly analyzed utilizing the bioluminescent activity of the LUC gene that has been integrated into the parasite’s ribosomal SSU RNA locus.  Cell proliferation and cytotoxicity of the mammalian cells is analyzed using alamarBlue®.  Our results showed that 3 of the 126 drugs tested provided sufficient parasiticidal effects with the absence of harmful cytotoxicity to mammalian cells, showing potential for use as chemotherapeutic agents against Leishmaniasis.  These 3 drugs are currently being researched in detail and will soon be tested in vivo.
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