title: Caenorhabditis elegans is a useful model for anthelmintic discovery.
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.
authors.affiliation: The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada M5S 3E1.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Burns
authors.affiliation: The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada M5S 3E1.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Genna M
authors.initials: GM
authors.lastname: Luciani
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, and Harvard Stem Cell Institute, Boston, Massachusetts 02115, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Musso
authors.affiliation: The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada M5S 3E1.
authors.forename: Rachel
authors.initials: R
authors.lastname: Bagg
authors.affiliation: The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada M5S 3E1.
authors.forename: May
authors.initials: M
authors.lastname: Yeo
authors.affiliation: The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada M5S 3E1.
authors.forename: Yuqian
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada M5S 3E1.
authors.forename: Luckshi
authors.initials: L
authors.lastname: Rajendran
authors.affiliation: The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada M5S 3E1.
authors.forename: John
authors.initials: J
authors.lastname: Glavin
authors.affiliation: The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada M5S 3E1.
authors.forename: Robert
authors.initials: R
authors.lastname: Hunter
authors.affiliation: Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4Z6.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Redman
authors.affiliation: Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4Z6.
authors.forename: Susan
authors.initials: S
authors.lastname: Stasiuk
authors.affiliation: The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada M5S 3E1.
authors.forename: Michael
authors.initials: M
authors.lastname: Schertzberg
authors.affiliation: Department of Biochemistry, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8.
authors.forename: G
authors.initials: G
authors.lastname: Angus McQuibban
authors.affiliation: Center for Discovery and Innovation in Parasitic Diseases and Department of Pathology, University of California, San Francisco, California 94158, USA.
authors.forename: Conor R
authors.initials: CR
authors.lastname: Caffrey
authors.affiliation: Center for Plant Cell Biology, Department of Botany and Plant Sciences, University of California, Riverside, California 92521, USA.
authors.forename: Sean R
authors.initials: SR
authors.lastname: Cutler
authors.affiliation: Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada H3T 1J4.
authors.forename: Mike
authors.initials: M
authors.lastname: Tyers
authors.affiliation: Department of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Guri
authors.initials: G
authors.lastname: Giaever
authors.affiliation: Department of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Corey
authors.initials: C
authors.lastname: Nislow
authors.affiliation: The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada M5S 3E1.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Andy G
authors.initials: AG
authors.lastname: Fraser
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, and Harvard Stem Cell Institute, Boston, Massachusetts 02115, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Calum A
authors.initials: CA
authors.lastname: MacRae
authors.affiliation: Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4Z6.
authors.forename: John
authors.initials: J
authors.lastname: Gilleard
authors.affiliation: The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada M5S 3E1.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8.|Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Roy
mesh_terms: D000818:Animals; D000871:Anthelmintics / Q000737:chemistry / Q000494:pharmacology*; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics; D042963:Electron Transport Complex II / Q000037:antagonists & inhibitors / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010802:Phylogeny; D011487:Protein Conformation; D013045:Species Specificity; D013329:Structure-Activity Relationship; D015027:Zebrafish
chemical_list: D000871:Anthelmintics; D029742:Caenorhabditis elegans Proteins; D042963:Electron Transport Complex II