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Selective control of parasitic nematodes using bioactivated nematicides


Parasitic nematodes are a major threat to global food security, particularly as the world amasses 10 billion people amid limited arable land1,2,3,4. Most traditional nematicides have been banned owing to poor nematode selectivity, leaving farmers with inadequate means of pest control4,5,6,7,8,9,10,11,12. Here we use the model nematode Caenorhabditis elegans to identify a family of selective imidazothiazole nematicides, called selectivins, that undergo cytochrome-p450-mediated bioactivation in nematodes. At low parts-per-million concentrations, selectivins perform comparably well with commercial nematicides to control root infection by Meloidogyne incognita, a highly destructive plant-parasitic nematode. Tests against numerous phylogenetically diverse non-target systems demonstrate that selectivins are more nematode-selective than most marketed nematicides. Selectivins are first-in-class bioactivated nematode controls that provide efficacy and nematode selectivity.

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Fig. 1: The selectivins.
Fig. 2: Selectivins are bioactivated nematicides.
Fig. 3: Selectivins are bioactivated to a toxic electrophile.
Fig. 4: Selectivin-A and selectivin-E are lead nematicides for plant-parasitic nematode control.
Fig. 5: M. incognita CYP4731A3 bioactivates selectivin-A.

Data availability

Data are available for Figs. 15 and Extended Data Figs. 13 and 4. Any other data that support the conclusions of this manuscript are available upon request. Source data are provided with this paper.

Code availability

The Python and R code used to generate the dose–response heatmaps and the HPLC chromatogram heatmaps have been published72.


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Free-living nematode strains were provided by the CGC (University of Minnesota), M.-A. Félix (Institute of Biology of the Ecole Normale Supérieure, Paris, France) and R. Rae (Liverpool John Moores University, Liverpool, UK). M.hapla was provided by B. Mimee at Agriculture and Agri-food Canada in Saint-Jean-sur-Richelieu, Quebec, Canada. MS analyses were performed by staff at the Advanced Instrumentation for Molecular Structure Mass Spectrometry Laboratory in the Department of Chemistry at the University of Toronto, Canada. NMR analyses were performed by staff at the CSICOMP NMR Facility in the Department of Chemistry at the University of Toronto, Canada. Many thanks to D. Colwell and D. Gray at the Lethbridge and Agri-Food Canada Research Centre for supplying faeces from infected calves for C.oncophora egg collection; K. Yoshioka at the University of Toronto, Canada, for P.simiae WSC417; J. Goldstone from the Woods Hole Oceanographic Institution for providing the M.incognita cyp gene names; B. Ciruna for the gift of NACET; G. Brown for the culture of S.cerevisiae; B. Derry for helpful comments on the manuscript; and N. Robbins from L. Cowen’s laboratory for comments on the work. The following grants supported this work: CIHR grants (313296 and 173448), an NSERC i2i grant (555963-20), a David Dime Grant, and a Canada Research Chair (Tier 1) to P.J.R.; a NSERC grant (RGPIN-2020-04168) to M.L.; a CIHR Foundation grant (FDN-154288) and a Canada Research Chair (Tier 1) to L.E.C.; an EvoFunPath fellowship from the NSERC CREATE program (555337-2021) to E.P.; a CIHR project grant (303157) to I.S. C.A.M.F. is supported by the Alberta Innovates Technology Fund (G2016000681). J.S.G. is supported by a NSERC discovery grant (RGPIN-2021-02489), and by the NSERC-CREATE Host–Parasite Interactions Program graduate training programme at the University of Calgary.

Author information

Authors and Affiliations



Unless otherwise noted, all experiments were carried out in the laboratory of P.J.R. All free-living nematode dose–response experiments were carried out by A.R.B. A.R.B. performed the HPLC-based metabolism experiments and analysed all related MS data. A.R.B. performed the NACET experiments. B.M.P., E.M.R. and A.R.B. performed the C. oncophora dose–response experiments in J.S.G.’s laboratory. S.cerevisiae work was done by A.R.B., J.K. and B.C. M.incognita bioinformatics was done by J.K. B.C. performed the yeast-based M.incognita CYP expression screen, and data were analysed by A.R.B. J.S. performed the HEK293 cell dose–response assays in I.S.’s laboratory. J.T. (in the laboratory of H.M.K.) and J.R.V. (in the laboratory of J.J.D.) performed the zebrafish dose–response assays. S.M. and S.W.C. performed the HepaRG cell dose–response experiments in S.A.M.’s laboratory. E.P. performed the C.albicans assays in L.E.C.’s laboratory. In the laboratory of S.R.C., A.S.V. performed the Arabidopsis greening assays. A.R.B performed the P.simiae dose–response experiments. C.A.M.F. and Q.X. carried out the mouse experiments. A.R.B. performed the metabolite purification for NMR analyses. R.J.B. carried out the selectivin syntheses and characterization in M.L.’s laboratory, and helped with metabolite NMR data analyses. A.R.B. performed the C.elegans cyp RNAi screen. M.H.M. carried out the in vitro M.incognita assays in S.L.F.M.’s laboratory. M.K. carried out the in vitro M.chitwoodi assays and the M.incognita soil-based reproduction assays in tomato plants in the laboratory of I.Z. A.R.B. and J.K. carried out the M.hapla assays. D.melanogaster experiments were carried out by C.H. and A.R.B. in the laboratories of P.J.R. and H.M.K. The genetics screens for resistant mutants were performed by A.R.B. The project was conceived by A.R.B. and P.J.R. The manuscript was written by A.R.B. and P.J.R.

Corresponding authors

Correspondence to Andrew R. Burns or Peter J. Roy.

Ethics declarations

Competing interests

L.E.C. is a co-founder and shareholder in Bright Angel Therapeutics, a platform company for development of new antifungal therapeutics. L.E.C. is a consultant for Boragen, a small-molecule development company focused on leveraging the specific chemical properties of boron chemistry for crop protection and animal health. L.E.C. is a Science Advisor for Kapoose Creek, a company that harnesses the therapeutic potential of fungi. Mention of trade names or commercial products in this publication is solely for the purpose of providing specific information and does not imply recommendation or endorsement by the US Department of Agriculture. USDA is an equal opportunity provider and employer. The University of Toronto is pursuing patent protection related to the use of selectivions as nematacides for which two national phase applications, US Patent Application 17/624,629, and Canadian Patent Application 3,146,085, are currently under prosecution and list A.R.B., M.L., R.B. and P.J.R. as inventors. A patent application, listing A.R.B., J.K., B.C., and P.J.R. as inventors, is under preparation for the use of yeast-based expression systems for the identification of bioactivated nematacides, insecticides, pesticides and drug leads. The patent application will be soon filed listing the inventors and the University of Toronto as applicants.

Peer review

Peer review information

Nature thanks Johan Desaeger, Timothy Geary, Fredd Vergara and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

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Extended data figures and tables

Extended Data Fig. 1 The selectivin-A imidazole-thiol metabolite is not nematicidal.

a, Mass spectrometry (MS) data for the M4 metabolite HPLC fraction and untreated control fraction, as well as MS/MS data for the 418.99 mass. The proposed M4 disulfide structure is shown, along with the protonated imidazole-thiol monomer structure resulting from fragmentation. b, A proposed metabolic pathway producing the imidazole-thiol metabolite (ITM) which oxidizes to form M4/ITM disulfide (ITM-DiS). Imidazothiazole ring opening is likely CYP-dependent. c, Biomass-normalized and background-corrected HPLC chromatograms for lysates of selectivin-A-treated L1 worms lysed ± iodoacetamide (IAA). Peaks corresponding to selectivin-A (sel-A), metabolites M1-M4, and alkylated ITM (ITM-alk) are indicated. d, MS data for the ITM-alk HPLC fraction and untreated control fraction. e, HPLC-DAD quantification of selectivin-A, M1-M4, and ITM-alk in the lysates of selectivin-A-treated L1 worms lysed ± IAA (n = 3 biological replicates with 200,000 worms per replicate). Area under the curve (AUC) for metabolites M1-M3 and ITM-alk was calculated at 260 nm, and at 300 nm for M4. Data are presented as mean ± SEM. For each analyte, unpaired one-tailed Student’s t-tests were performed comparing the means of the ± IAA conditions. P-values are shown. f, Dose-response for C. elegans L1s treated with selectivins or commercially-sourced ITM. g, Biomass-normalized and background-corrected HPLC chromatograms for lysates of L1 worms incubated in commercially-sourced ITM, lysed ± IAA. The top chromatogram is the ITM standard injected directly onto the column, and is not normalized or corrected. ITM oxidizes to ITM-DiS prior to HPLC analysis. ITM-DiS and ITM-alk peaks are indicated. h, HPLC-DAD quantification of M4/ITM-DiS and ITM-alk in the lysates of 100 µM selectivin-A-treated or 100 µM ITM-treated L1 worms, lysed ± IAA (n = 3 biological replicates with 200,000 worms per replicate). AUC was calculated at 260 nm. Data are presented as mean ± SEM.

Source Data

Extended Data Fig. 2 NMR spectra for HPLC-purified selectivin-A metabolite M2.

a, 1H NMR spectra. The structure of M2 with all carbon and heteroatom assignments is given. The top number in each multiplet box corresponds to the carbon that the proton is connected to. 1H NMR (700 MHz, cd3od) δ 8.02 (s, 1H), 7.82 – 7.78 (m, 2H), 7.42 – 7.37 (m, 2H), 5.98 (dd, J = 7.9, 2.2 Hz, 1H), 4.74 (dd, J = 7.6, 5.3 Hz, 1H), 4.66 (dd, J = 14.9, 8.0 Hz, 1H), 3.86 (s, 2H), 3.81 (dd, J = 14.9, 2.2 Hz, 1H), 3.62 (t, J = 6.2 Hz, 1H), 3.23 (dd, J = 14.2, 5.3 Hz, 1H), 3.08 (dd, J = 14.1, 7.6 Hz, 1H), 2.54 (ddd, J = 15.9, 7.9, 6.6 Hz, 1H), 2.48 (dt, J = 15.8, 6.6 Hz, 1H), 2.16 – 2.05 (m, 2H), 1.97 (s, 3H). b, 1H-1H COSY NMR spectra. c, 1H-13C HSQC NMR spectra. d, 1H-13C HMBC NMR spectra.

Extended Data Fig. 3 Selectivin bioactivation is nematode-specific.

a and b, Biomass-normalized and background-corrected HPLC chromatograms of lysates (a) and incubation buffers (b) from C. elegans (Ce), C. briggsae (Cb), P. pacificus (Pp), Rhabditophanes sp. KR3021 (KR), M. incognita (Mi), D. melanogaster (Dm), and D. rerio (Dr) larvae, as well as S. cerevisiae (Sc) cells, incubated in 100 µM selectivin-A. Selectivin-A and metabolite peaks are indicated. c, Total detectable production of M1 + M2 + M3 in lysate and buffer for each of the seven species tested. d, M2 tissue accumulation in each species tested. e, Unmodified selectivin-A tissue accumulation in each of the test species. AUC is area under the curve at 260 nm. Data are presented as mean ± SEM. For c and d, unpaired one-tailed Student’s t-tests were performed for all pairwise comparisons of means. The means sharing a letter are statistically indistinguishable (p > 0.01). The p-values for each comparison in c and d can be found in the Statistical Information subsection of the Methods. For e, unpaired one-tailed Student’s t-tests were performed relative to the C. elegans mean. P-values are shown. For c-e, n = 4 biological replicates for Ce, Cb, Pp, and Dr, and n = 3 biological replicates for KR, Mi, Sc, and Dm.

Source Data

Extended Data Fig. 4 Selectivin treatment generally increases the root weights of tomato plants challenged with nematode infection.

The effects of 11 selectivin analogs and 4 commercial nematicides on the root weights of tomato plants challenged with M. incognita infection is shown. Root weight values are percent of untreated control. For each analog, aqueous molar concentration, parts-per-million soil concentration, and kilograms-per-hectare values are shown. The R-groups for each selectivin analog are indicated (see Fig. 1a for the selectivin core scaffold and R-group positions). Data are presented as mean ± SEM.

Source Data

Extended Data Fig. 5 Free-living nematodes likely detoxify selectivin-E via hydroxylation and subsequent phosphoglucosidation.

a, Structure of selectivin-E (sel-E) with exact mass. b-c, Raw HPLC chromatograms for lysates of C. elegans and P. pacificus L1 worms incubated in 100 µM selectivin-E or DMSO alone (untreated). The top chromatogram is the selectivin-E standard injected directly onto the column. The unmodified selectivin-E parent compound and selectivin-E metabolites E-M1, E-M2, and E-M3 are indicated. c, Mass spectrometry (MS) data for the E-M1, E-M2, and E-M3 HPLC fractions and corresponding untreated control fractions. Raw MS counts are shown for the most abundant masses identified in the mass spectra that are not detectable in the corresponding untreated control fractions. Raw counts were taken from centroid plots of the raw mass spectra. Counts below 1 × 103 were considered not detectable (nd). Based on the presumptive masses of the three metabolites we predict that E-M1 is a hydroxylated metabolite of selectivin-E, E-M2 is an O-linked glucoside of selectivin-E, and E-M3 is an O-linked phosphoglucoside. Molecular formulas are indicated for the predicted metabolite structures, as well as exact masses, P. pacificus experimental accurate masses, and the ppm difference between the two. A ppm difference of less than 5 ppm suggests that the molecular formulae are correct. Ce, C. elegans; Pp, P. pacificus.

Extended Data Table 1 Anthelmintic/nematicide-resistant mutants are sensitive to the selectivins
Extended Data Table 2 Genetic resistance to selectivins is difficult to achieve
Extended Data Table 3 Summary of MS data for selectivin-A metabolites from lysates
Extended Data Table 4 HPLC solvent and flow rate gradients

Supplementary information

Reporting Summary

Peer Review File

Supplementary Table 1

Accurate mass and exact mass values for the selectivin-A metabolites.

Supplementary Table 2

C. elegans cyp RNAi screen data.

Supplementary Table 3

Identity matrix for the 31 M.incognita CYP protein sequences Identified from the v3 genome.

Supplementary Table 4

C. elegans CYP-35C1, C. elegans EMB-8 and M.incognita CYP cDNA sequences codon-optimized for yeast expression.

Supplementary Table 5

Yeast-based M.incognita cyp expression screen data.

Supplementary Table 6

M.incognita gene read counts and expression ranks obtained from RNA sequencing analysis from ref. 43.

Source data

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Burns, A.R., Baker, R.J., Kitner, M. et al. Selective control of parasitic nematodes using bioactivated nematicides. Nature (2023).

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