Caenorhabditis elegans is a useful model for anthelmintic discovery. Nat Commun 2015 Jun 25;6:7485
Date
06/26/2015Pubmed ID
26108372Pubmed Central ID
PMC4491176DOI
10.1038/ncomms8485Scopus ID
2-s2.0-84932611592 (requires institutional sign-in at Scopus site) 198 CitationsAbstract
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.
Author List
Burns AR, Luciani GM, Musso G, Bagg R, Yeo M, Zhang Y, Rajendran L, Glavin J, Hunter R, Redman E, Stasiuk S, Schertzberg M, Angus McQuibban G, Caffrey CR, Cutler SR, Tyers M, Giaever G, Nislow C, Fraser AG, MacRae CA, Gilleard J, Roy PJAuthor
Luckshi Rajendran MD Assistant Professor in the Surgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAnthelmintics
Caenorhabditis elegans
Caenorhabditis elegans Proteins
Drug Resistance
Electron Transport Complex II
HEK293 Cells
Humans
Models, Molecular
Molecular Structure
Phylogeny
Protein Conformation
Species Specificity
Structure-Activity Relationship
Zebrafish
