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Caenorhabditis elegans is a useful model for anthelmintic discovery.

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 PJ - Nat Commun (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada M5S 3E1.

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.

No MeSH data available.


Related in: MedlinePlus

Molecules that kill C. elegans are enriched for those that are lethal to parasitic nematodes.(a) Flow chart outlining the multi-organism small-molecule screening pipeline. (b) Venn diagram showing the overlap of wactive library molecules that kill C. elegans, Cooperia oncophora and H. contortus. (c) Chart showing the enrichment of molecules that kill Cooperia, H. contortus, zebrafish, and HEK cells in the set of 275 C. elegans-lethals, relative to a randomly selected set of 182 compounds.
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f1: Molecules that kill C. elegans are enriched for those that are lethal to parasitic nematodes.(a) Flow chart outlining the multi-organism small-molecule screening pipeline. (b) Venn diagram showing the overlap of wactive library molecules that kill C. elegans, Cooperia oncophora and H. contortus. (c) Chart showing the enrichment of molecules that kill Cooperia, H. contortus, zebrafish, and HEK cells in the set of 275 C. elegans-lethals, relative to a randomly selected set of 182 compounds.

Mentions: To identify nematicidal compounds, we screened 67,012 commercially available small drug-like molecules for those that induce obvious phenotypes in C. elegans at a concentration of 60 μM or less (see Fig. 1a and Supplementary Data 1). From our preliminary screens, we identified 627 bioactive molecules that we call ‘worm actives' or ‘wactives'. Rescreening revealed 275 wactives that kill C. elegans at a concentration of 60 μM or less (see Supplementary Data 1). By contrast, none of the 182 molecules chosen at random from the set of 67,012 compounds killed C. elegans (see Supplementary Data 1).


Caenorhabditis elegans is a useful model for anthelmintic discovery.

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 PJ - Nat Commun (2015)

Molecules that kill C. elegans are enriched for those that are lethal to parasitic nematodes.(a) Flow chart outlining the multi-organism small-molecule screening pipeline. (b) Venn diagram showing the overlap of wactive library molecules that kill C. elegans, Cooperia oncophora and H. contortus. (c) Chart showing the enrichment of molecules that kill Cooperia, H. contortus, zebrafish, and HEK cells in the set of 275 C. elegans-lethals, relative to a randomly selected set of 182 compounds.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4491176&req=5

f1: Molecules that kill C. elegans are enriched for those that are lethal to parasitic nematodes.(a) Flow chart outlining the multi-organism small-molecule screening pipeline. (b) Venn diagram showing the overlap of wactive library molecules that kill C. elegans, Cooperia oncophora and H. contortus. (c) Chart showing the enrichment of molecules that kill Cooperia, H. contortus, zebrafish, and HEK cells in the set of 275 C. elegans-lethals, relative to a randomly selected set of 182 compounds.
Mentions: To identify nematicidal compounds, we screened 67,012 commercially available small drug-like molecules for those that induce obvious phenotypes in C. elegans at a concentration of 60 μM or less (see Fig. 1a and Supplementary Data 1). From our preliminary screens, we identified 627 bioactive molecules that we call ‘worm actives' or ‘wactives'. Rescreening revealed 275 wactives that kill C. elegans at a concentration of 60 μM or less (see Supplementary Data 1). By contrast, none of the 182 molecules chosen at random from the set of 67,012 compounds killed C. elegans (see Supplementary Data 1).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada M5S 3E1.

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.

No MeSH data available.


Related in: MedlinePlus