Drug Discovery for Schistosomiasis: Hit and Lead Compounds Identified in a Library of Known Drugs by Medium-Throughput Phenotypic Screening

Abdulla, Maha-Hamadien; Ruelas, Debbie S.; Wolff, Brian; Snedecor, June; Lim, Kee-Chong; Xu, Fengyun; Renslo, Adam R.; Williams, Janice; McKerrow, James H.; Caffrey, Conor R.
July 2009
PLoS Neglected Tropical Diseases;Jul2009, Vol. 3 Issue 7, p1
Academic Journal
Praziquantel (PZQ) is the only widely available drug to treat schistosomiasis. Given the potential for drug resistance, it is prudent to search for novel therapeutics. Identification of anti-schistosomal chemicals has traditionally relied on phenotypic (whole organism) screening with adult worms in vitro and/or animal models of disease-tools that limit automation and throughput with modern microtiter plate-formatted compound libraries. Methods: A partially automated, three-component phenotypic screen workflow is presented that utilizes at its apex the schistosomular stage of the parasite adapted to a 96-well plate format with a throughput of 640 compounds per month. Hits that arise are subsequently screened in vitro against adult parasites and finally for efficacy in a murine model of disease. Two GO/NO GO criteria filters in the workflow prioritize hit compounds for tests in the animal disease model in accordance with a target drug profile that demands short-course oral therapy. The screen workflow was inaugurated with 2,160 chemically diverse natural and synthetic compounds, of which 821 are drugs already approved for human use. This affords a unique starting point to 'reposition' (re-profile) drugs as anti-schistosomals with potential savings in development timelines and costs. Findings: Multiple and dynamic phenotypes could be categorized for schistosomula and adults in vitro, and a diverse set of 'hit' drugs and chemistries were identified, including anti-schistosomals, anthelmintics, antibiotics, and neuromodulators. Of those hits prioritized for tests in the animal disease model, a number of leads were identified, one of which compares reasonably well with PZQ in significantly decreasing worm and egg burdens, and disease-associated pathology. Data arising from the three components of the screen are posted online as a community resource. Conclusions: To accelerate the identification of novel anti-schistosomals, we have developed a partially automated screen workflow that interfaces schistosomula with microtiter plate-formatted compound libraries. The workflow has identified various compounds and drugs as hits in vitro and leads, with the prescribed oral efficacy, in vivo. Efforts to improve throughput, automation, and rigor of the screening workflow are ongoing.


Related Articles

  • Whole Organism High-Content Screening by Label-Free, Image-Based Bayesian Classification for Parasitic Diseases. Paveley, Ross A.; Mansour, Nuha R.; Hallyburton, Irene; Bleicher, Leo S.; Benn, Alex E.; Mikic, Ivana; Guidi, Alessandra; Gilbert, Ian H.; Hopkins, Andrew L.; Bickle, Quentin D. // PLoS Neglected Tropical Diseases;Jul2012, Vol. 6 Issue 7, p1 

    Sole reliance on one drug, Praziquantel, for treatment and control of schistosomiasis raises concerns about development of widespread resistance, prompting renewed interest in the discovery of new anthelmintics. To discover new leads we designed an automated label-free, high content-based, high...

  • Present-day anthelmintics and perspectives on future new targets. Taman, Amira; Azab, Manar // Parasitology Research;Jul2014, Vol. 113 Issue 7, p2425 

    In absence of vaccines for the majority of helminths, chemotherapy is still the mainstay for controlling human helminthiases. However, a limited number of drugs are available in the market to combat parasitic helminths in human. Besides, the development and spread of drug resistance have...

  • Staphylococcus aureus Isolated from Endophthalmitis Are Hospital-Acquired Based on Panton-Valentine Leukocidin and Antibiotic Susceptibility Testing. Rarey, Kristin A.; Shanks, Robert M.Q.; Romanowski, Eric G.; Mah, Francis S.; Kowalski, Regis P. // Journal of Ocular Pharmacology & Therapeutics;Feb2012, Vol. 28 Issue 1, p12 

    Purpose: Staphylococcus aureus (SA) endophthalmitis is generally a postsurgical infection with an undefined source of entry. Hospital-acquired (HA) SA infections are associated with multi-antibiotic resistance and absence of the Panton-Valentine Leukocidin (PVL) toxin. Community-acquired (CA) SA...

  • A Novel High Throughput Assay for Anthelmintic Drug Screening and Resistance Diagnosis by Real-Time Monitoring of Parasite Motility. Smout, Michael J.; Kotze, Andrew C.; McCarthy, James S.; Loukas, Alex // PLoS Neglected Tropical Diseases;Nov2010, Vol. 4 Issue 11, p1 

    Background: Helminth parasites cause untold morbidity and mortality to billions of people and livestock. Anthelmintic drugs are available but resistance is a problem in livestock parasites, and is a looming threat for human helminths. Testing the efficacy of available anthelmintic drugs and...

  • Current chemotherapy arsenal for schistosomiasis mansoni: alternatives and challenges. Rashad Abdul-Ghani; Naguiba Loutfy; Amel Sahn; Azza Hassan // Parasitology Research;Apr2009, Vol. 104 Issue 5, p955 

    Abstract  Schistosomiasis still represents a major health problem in many tropical and subtropical countries despite continuing control efforts. Due to the unavailability of a vaccine that is practically applicable to humans, the use of chemotherapy is the mainstay of...

  • In vivo schistosomicidal activity of three novels 8-hydroxyquinoline derivatives against adult and immature worms of Schistosoma mansoni. Allam, Gamal; Eweas, Ahmad; Abuelsaad, Abdelaziz // Parasitology Research;Sep2013, Vol. 112 Issue 9, p3137 

    Schistosomiasis control is widely dependent on a single drug, praziquantel (PZQ). The potential for development of resistance to PZQ has justified the search for new alternative chemotherapies. In a previous study, we have been reported that three of 8-hydroxyquinoline derivatives namely:...

  • Praziquantel: A Major Advance in Anthelminthic Therapy. Pearson, Richard D.; Guerrant, Richard L. // Annals of Internal Medicine;Aug83, Vol. 99 Issue 2, p195 

    Discusses the therapeutic use of praziquantel for the treatment against all forms of schistosomiasis. Pharmacology of the anthelmintic agent; Details of its toxicity; Information on the treatment of schistosomiasis and other trematodes and chestode infections.

  • Production trials involving use of the FAMACHA system for haemonchosis in sheep: preliminary results. VAN WYK, J. A. // Onderstepoort Journal of Veterinary Research;Dec2008, Vol. 75 Issue 4, p331 

    The article analyzes the preliminary results of production trials involving the use of the FAMACHA system for haemonchosis in sheep. According to the author, in three trials conducted on two separate farms, the production of sheep treated for naturally acquired haemonchosis using the FAMACHA...

  • Assessment of Anthelmintic Efficacy of Mebendazole in School Children in Six Countries Where Soil-Transmitted Helminths Are Endemic. Levecke, Bruno; Montresor, Antonio; Albonico, Marco; Ame, Shaali M.; Behnke, Jerzy M.; Bethony, Jeffrey M.; Noumedem, Calvine D.; Engels, Dirk; Guillard, Bertrand; Kotze, Andrew C.; Krolewiecki, Alejandro J.; McCarthy, James S.; Mekonnen, Zeleke; Periago, Maria V.; Sopheak, Hem; Tchuem-Tchuenté, Louis-Albert; Duong, Tran Thanh; Huong, Nguyen Thu; Zeynudin, Ahmed; Vercruysse, Jozef // PLoS Neglected Tropical Diseases;Oct2014, Vol. 8 Issue 10, p1 

    Background: Robust reference values for fecal egg count reduction (FECR) rates of the most widely used anthelmintic drugs in preventive chemotherapy (PC) programs for controlling soil-transmitted helminths (STHs; Ascaris lumbricoides, Trichuris trichiura, and hookworm) are still lacking....


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics