title: Using C. elegans Forward and Reverse Genetics to Identify New Compounds with Anthelmintic Activity.
abstract: BACKGROUND
  The lack of new anthelmintic agents is of growing concern because it affects human health and our food supply, as both livestock and plants are affected. Two principal factors contribute to this problem. First, nematode resistance to anthelmintic drugs is increasing worldwide and second, many effective nematicides pose environmental hazards. In this paper we address this problem by deploying a high throughput screening platform for anthelmintic drug discovery using the nematode Caenorhabditis elegans as a surrogate for infectious nematodes. This method offers the possibility of identifying new anthelmintics in a cost-effective and timely manner.
  
  
  RESULTS
  Using our high throughput screening platform we have identified 14 new potential anthelmintics by screening more than 26,000 compounds from the Chembridge and Maybridge chemical libraries. Using phylogenetic profiling we identified a subset of the 14 compounds as potential anthelmintics based on the relative sensitivity of C. elegans when compared to yeast and mammalian cells in culture. We showed that a subset of these compounds might employ mechanisms distinct from currently used anthelmintics by testing diverse drug resistant strains of C. elegans. One of these newly identified compounds targets mitochondrial complex II, and we used structural analysis of the target to suggest how differential binding of this compound may account for its different effects in nematodes versus mammalian cells.
  
  
  CONCLUSIONS
  The challenge of anthelmintic drug discovery is exacerbated by several factors; including, 1) the biochemical similarity between host and parasite genomes, 2) the geographic location of parasitic nematodes and 3) the rapid development of resistance. Accordingly, an approach that can screen large compound collections rapidly is required. C. elegans as a surrogate parasite offers the ability to screen compounds rapidly and, equally importantly, with specificity, thus reducing the potential toxicity of these compounds to the host and the environment. We believe this approach will help to replenish the pipeline of potential nematicides.
authors.affiliation: Department of Zoology and Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada.|Department of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Mathew
authors.affiliation: Department of Zoology and Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada.|Department of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Neal D
authors.initials: ND
authors.lastname: Mathew
authors.affiliation: Department of Zoology and Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Angela
authors.initials: A
authors.lastname: Miller
authors.affiliation: Department of Zoology and Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Mike
authors.initials: M
authors.lastname: Simpson
authors.affiliation: Department of Zoology and Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Vinci
authors.initials: V
authors.lastname: Au
authors.affiliation: Department of Zoology and Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Garland
authors.affiliation: Universite de Poitiers, Poitiers, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Gestin
authors.affiliation: Department of Zoology and Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Edgley
authors.affiliation: Department of Zoology and Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada.|Department of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Stephane
authors.initials: S
authors.lastname: Flibotte
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Aruna
authors.initials: A
authors.lastname: Balgi
authors.affiliation: Department of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Chiang
authors.affiliation: Department of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Guri
authors.initials: G
authors.lastname: Giaever
authors.affiliation: Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Pamela
authors.initials: P
authors.lastname: Dean
authors.affiliation: Summerland Research and Development Centre, Agriculture and Agri-Food Canada, Summerland, British Columbia, Canada.
authors.forename: Audrey
authors.initials: A
authors.lastname: Tung
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Roberge
authors.affiliation: Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Calvin
authors.initials: C
authors.lastname: Roskelley
authors.affiliation: Summerland Research and Development Centre, Agriculture and Agri-Food Canada, Summerland, British Columbia, Canada.
authors.forename: Tom
authors.initials: T
authors.lastname: Forge
authors.affiliation: Department of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Corey
authors.initials: C
authors.lastname: Nislow
authors.affiliation: Department of Zoology and Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Donald
authors.initials: D
authors.lastname: Moerman
mesh_terms: D000818:Animals; D000969:Antinematodal Agents / Q000494:pharmacology*; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D004353:Drug Evaluation, Preclinical; D006801:Humans; D009348:Nematoda / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D009349:Nematode Infections / Q000188:drug therapy / Q000469:parasitology*; D059386:Reverse Genetics
chemical_list: D000969:Antinematodal Agents