Cyprocide selectively kills nematodes via cytochrome P450 bioactivation

  • Nat Commun. 2024 Jul 2;15(1):5529. doi: 10.1038/s41467-024-49738-4.
Jessica Knox  1  2 ,  Andrew R Burns  1  2 ,  Brittany Cooke  1  2 ,  Savina R Cammalleri  1  2 ,  Megan Kitner  3 ,  Justin Ching  4 ,  Jack M P Castelli  1  2 ,  Emily Puumala  1 ,  Jamie Snider  2 ,  Emily Koury  5 ,  J B Collins  5 ,  Salma Geissah  1  6 ,  James J Dowling  1  6 ,  Erik C Andersen  7 ,  Igor Stagljar  1  2  8  9 ,  Leah E Cowen  1 ,  Mark Lautens  4 ,  Inga Zasada  3 ,  Peter J Roy  10  11  12
Affiliations
  • 1. Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
  • 2. Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada.
  • 3. United States Department of Agriculture - Agricultural Research Service, Horticultural Crops Disease and Pest Management Research Unit, Corvallis, OR, USA.
  • 4. Davenport Research Laboratories, Department of Chemistry, University of Toronto, Toronto, ON, Canada.
  • 5. Molecular Biosciences, Northwestern University, Evanston, IL, USA.
  • 6. Division of Neurology and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
  • 7. Department of Biology, Johns Hopkins University, Baltimore, MD, USA.
  • 8. Department of Biochemistry, University of Toronto, Toronto, ON, Canada.
  • 9. Mediterranean Institute for Life Sciences, Meštrovićevo Šetalište 45, HR-21000, Split, Croatia.
  • 10. Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. [email protected].
  • 11. Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada. [email protected].
  • 12. Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada. [email protected].
PMID: 38956039 DOI: 10.1038/s41467-024-49738-4
Abstract

Left unchecked, plant-parasitic nematodes have the potential to devastate crops globally. Highly effective but non-selective nematicides are justifiably being phased-out, leaving farmers with limited options for managing nematode infestation. Here, we report our discovery of a 1,3,4-oxadiazole thioether scaffold called Cyprocide that selectively kills nematodes including diverse species of plant-parasitic nematodes. Cyprocide is bioactivated into a lethal reactive electrophilic metabolite by specific nematode Cytochrome P450 enzymes. Cyprocide fails to kill organisms beyond nematodes, suggesting that the targeted lethality of this pro-nematicide derives from P450 substrate selectivity. Our findings demonstrate that Cyprocide is a selective nematicidal scaffold with broad-spectrum activity that holds the potential to help safeguard our global food supply.

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