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Compound Library Screening Using Giardia Lamblia High Throughput Viability Assay


Giardia lamblia is a human pathogen afflicting impoverished nations, and the most common cause of outbreaks of diarrhea in the United States. Giardia has been classified by the CDC as a category B bioterrorism organism. The favored anti giardiasis drugs in the US are metronidazole or tinidazole, compounds that have undesirable side effects. Moreover, increasing resistance to drug regimes and recurrence are a concern. It is thus clear that alternative drug treatments are needed. <P> We have developed a bioluminescence Giarida viability assay based on the trophozoites ATP content that is suitable for high throughput screening and miniaturized the assay for compound screening in 1536-well plates. We propose to screen the NIH compound library and investigate the selectivity of hit compounds using initially CHO cells and later CACO-2 cells. The minimum lethal concentration of selective compounds exhibiting low IC50 will be determined by re- growth experiments. For a few top hits, identification of the Giardia target will be undertaken and if successful, advanced to structure-based compound optimization.

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Public Health Relevance: Giardia lamblia is a human pathogen afflicting billions of people annually and a category B bioterrorism organism. Giardiasis treatments have undesirable side effects, recurrence, and increasing drug resistance. To facilitate discovery of better drugs, we have developed a Giardia viability assay and miniaturized it for high throughput compound screening. This assay will be used to screen the NIH compound library and identify compounds that kill Giardia trophozoites.

Herzberg, Osnat
University of Maryland - College Park
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