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Nat Commun. 2015 Jun 25;6:7485. doi: 10.1038/ncomms8485.

Caenorhabditis elegans is a useful model for anthelmintic discovery.

Author information

1
The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada M5S 3E1.
2
1] The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada M5S 3E1 [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
3
1] Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, and Harvard Stem Cell Institute, Boston, Massachusetts 02115, USA [2] Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
4
Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4Z6.
5
Department of Biochemistry, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8.
6
Center for Discovery and Innovation in Parasitic Diseases and Department of Pathology, University of California, San Francisco, California 94158, USA.
7
Center for Plant Cell Biology, Department of Botany and Plant Sciences, University of California, Riverside, California 92521, USA.
8
Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada H3T 1J4.
9
Department of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
10
1] The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada M5S 3E1 [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8 [3] Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada M5S 1A8.

Abstract

Parasitic nematodes infect one quarter of the world's population and impact all humans through widespread infection of crops and livestock. Resistance to current anthelmintics has prompted the search for new drugs. Traditional screens that rely on parasitic worms are costly and labour intensive and target-based approaches have failed to yield novel anthelmintics. Here, we present our screen of 67,012 compounds to identify those that kill the non-parasitic nematode Caenorhabditis elegans. We then rescreen our hits in two parasitic nematode species and two vertebrate models (HEK293 cells and zebrafish), and identify 30 structurally distinct anthelmintic lead molecules. Genetic screens of 19 million C. elegans mutants reveal those nematicides for which the generation of resistance is and is not likely. We identify the target of one lead with nematode specificity and nanomolar potency as complex II of the electron transport chain. This work establishes C. elegans as an effective and cost-efficient model system for anthelmintic discovery.

PMID:
26108372
PMCID:
PMC4491176
DOI:
10.1038/ncomms8485
[Indexed for MEDLINE]
Free PMC Article

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