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Identification of a family of species-selective complex I inhibitors as potential anthelmintics

Author

Listed:
  • Taylor Davie

    (University of Toronto
    Department of Molecular Genetics, University of Toronto)

  • Xènia Serrat

    (University of Toronto
    Department of Molecular Genetics, University of Toronto)

  • Lea Imhof

    (Swiss Tropical and Public Health Institute, Kreuzstrasse 2
    University of Basel)

  • Jamie Snider

    (University of Toronto
    Department of Molecular Genetics, University of Toronto)

  • Igor Štagljar

    (University of Toronto
    Department of Molecular Genetics, University of Toronto
    Mediterranean Institute for Life Sciences
    University of Toronto)

  • Jennifer Keiser

    (Swiss Tropical and Public Health Institute, Kreuzstrasse 2
    University of Basel)

  • Hiroyuki Hirano

    (RIKEN Center for Sustainable Resource Science)

  • Nobumoto Watanabe

    (RIKEN Center for Sustainable Resource Science)

  • Hiroyuki Osada

    (RIKEN Center for Sustainable Resource Science
    Institute of Microbial Chemistry (BIKAKEN))

  • Andrew G. Fraser

    (University of Toronto
    Department of Molecular Genetics, University of Toronto)

Abstract

Soil-transmitted helminths (STHs) are major pathogens infecting over a billion people. There are few classes of anthelmintics and there is an urgent need for new drugs. Many STHs use an unusual form of anaerobic metabolism to survive the hypoxic conditions of the host gut. This requires rhodoquinone (RQ), a quinone electron carrier. RQ is not made or used by vertebrate hosts making it an excellent therapeutic target. Here we screen 480 structural families of natural products to find compounds that kill Caenorhabditis elegans specifically when they require RQ-dependent metabolism. We identify several classes of compounds including a family of species-selective inhibitors of mitochondrial respiratory complex I. These identified complex I inhibitors have a benzimidazole core and we determine key structural requirements for activity by screening 1,280 related compounds. Finally, we show several of these compounds kill adult STHs. We suggest these species-selective complex I inhibitors are potential anthelmintics.

Suggested Citation

  • Taylor Davie & Xènia Serrat & Lea Imhof & Jamie Snider & Igor Štagljar & Jennifer Keiser & Hiroyuki Hirano & Nobumoto Watanabe & Hiroyuki Osada & Andrew G. Fraser, 2024. "Identification of a family of species-selective complex I inhibitors as potential anthelmintics," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47331-3
    DOI: 10.1038/s41467-024-47331-3
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    References listed on IDEAS

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    1. Andrew R. Burns & Genna M. Luciani & Gabriel Musso & Rachel Bagg & May Yeo & Yuqian Zhang & Luckshika Rajendran & John Glavin & Robert Hunter & Elizabeth Redman & Susan Stasiuk & Michael Schertzberg &, 2015. "Caenorhabditis elegans is a useful model for anthelmintic discovery," Nature Communications, Nature, vol. 6(1), pages 1-11, November.
    2. Bingyi Chen & Siting Luo & Songxuan Zhang & Yingchen Ju & Qiong Gu & Jun Xu & Xiang-Lei Yang & Huihao Zhou, 2021. "Author Correction: Inhibitory mechanism of reveromycin A at the tRNA binding site of a class I synthetase," Nature Communications, Nature, vol. 12(1), pages 1-1, December.
    3. Bingyi Chen & Siting Luo & Songxuan Zhang & Yingchen Ju & Qiong Gu & Jun Xu & Xiang-Lei Yang & Huihao Zhou, 2021. "Inhibitory mechanism of reveromycin A at the tRNA binding site of a class I synthetase," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    4. Ronald Kaminsky & Pierre Ducray & Martin Jung & Ralph Clover & Lucien Rufener & Jacques Bouvier & Sandra Schorderet Weber & Andre Wenger & Susanne Wieland-Berghausen & Thomas Goebel & Noelle Gauvry & , 2008. "A new class of anthelmintics effective against drug-resistant nematodes," Nature, Nature, vol. 452(7184), pages 176-180, March.
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