Schistosomiasis is a tropical parasitic disease infecting over 200 million people. Treatment relies on a single drug, praziquantel (PZQ). In the absence of back-up drugs with PZQ's therapeutic spectrum, the risk of resistance to PZQ and eventual drug failure is a major concern. Traditional phenotypic screens, using adult- stage S. mansoni, are low-throughput and incompatible with modern high-throughput screen (HTS) systems. In keeping with the NIAID's mission, the present proposal aims to turn a newly developed, moderate- throughput phenotypic screen (MTS), into a fully automated, quantitative HTS to accelerate drug discovery for this infectious disease. The proposal involves three PIs with ongoing collaborations and respective biological, screening-technology and bio-computational skills who are focused on just this goal. As a first research track for this proposal, we will utilize in-house automation and a high-content screening (HCS) system to significantly increase throughput over our published MTS approach. The proposal will involve;expanding robotic plating of the parasite, developing protocols for bright-field and fluorescence-based microscopy and adapting commercial image-analysis software to identify (segment), quantitatively describe and track the motion of parasites with a view to prioritizing compounds for further pre-clinical development. Because commercial HCS analysis tools are not likely optimized for recording the complex and dynamic phenotypes displayed by this multicellular parasite, we will also pursue a second and parallel track of research. Specifically, we will develop de novo an automated image-analysis screening technology to define, identify, and quantify the range of phenotypic responses (morphological and behavioral) possible in this parasite. Ultimately, both the experimental and computation tracks will together produce a standardized HTS protocol and a comprehensive, quantitative suite of image-analysis programs to categorize parasite phenotypes. Such rigor will facilitate the screening of large numbers of potential compounds and their prioritization into the secondary and tertiary screening assays available in-house. We also intend to make the algorithmic framework including its methods and implementations, publicly available.

Public Health Relevance

The major goal of the project is to turn a moderate-throughput phenotypic screen (MTS) system for schistosomiasis, into a fully automated, quantitative high-throughput screen (HTS). By so doing, the rate of discovery of drugs to treat this global tropical disease will be increased.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Rogers, Martin J
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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