Cyprocide selectively kills nematodes via cytochrome P450 bioactivation.

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.

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 land1-4. Most traditional nematicides have been banned owing to poor nematode selectivity, leaving farmers with inadequate means of pest control4-12. 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.

Egg-laying and locomotory screens with C. elegans yield a nematode-selective small molecule stimulator of neurotransmitter release.

Nematode parasites of humans, livestock and crops dramatically impact human health and welfare. Alarmingly, parasitic nematodes of animals have rapidly evolved resistance to anthelmintic drugs, and traditional nematicides that protect crops are facing increasing restrictions because of poor phylogenetic selectivity. Here, we exploit multiple motor outputs of the model nematode C. elegans towards nematicide discovery. This work yielded multiple compounds that selectively kill and/or immobilize diverse nematode parasites. We focus on one compound that induces violent convulsions and paralysis that we call nementin. We find that nementin stimulates neuronal dense core vesicle release, which in turn enhances cholinergic signaling. Consequently, nementin synergistically enhances the potency of widely-used non-selective acetylcholinesterase (AChE) inhibitors, but in a nematode-selective manner. Nementin therefore has the potential to reduce the environmental impact of toxic AChE inhibitors that are used to control nematode infections and infestations.

Developmental Dynamics of Globodera ellingtonae in Field-Grown Potato.

Globodera ellingtonae is a recently described nematode parasite of potato, which is closely related to the economically significant potato cyst nematodes G. rostochiensis and G. pallida. Because of the close relationship of G. ellingtonae to the potato cyst nematodes, a greater understanding of its biology is critical. Two experiments were conducted in Oregon to explore the developmental biology of G. ellingtonae in field-grown potato. The first experiment was conducted in 2013 and 2014 to determine the developmental timing of G. ellingtonae life stages and reproduction by inoculating potato with soil containing cysts followed by weekly collection of soil and root samples. Life stages; second-stage juveniles (J2) in soil and roots, third-stage juveniles (J3) and fourth-stage (J4) females and males in roots, males and females or cysts in soil, and egg number and developmental state were quantified. Normalizing across years using accumulated developmental degree days above 6°C (DD6), J2 of G. ellingtonae were found in soil from 41 to 588 DD6; two peaks of J2 invasion of roots were observed. The first adult females were observed at 387 and 449 DD6 in 2013 and 2014, respectively. The next generation of eggs was first observed from 675 to 854 DD6 and 50% egg development (containing a vermiform juvenile) occurred at approximately 920 DD6. A second J2 hatch was observed in both years at 927 to 1,073 DD6. The developmental dynamics of G. ellingtonae observed here are similar to those reported for G. rostochiensis and G. pallida from several geographical locations. In the second experiment, the effect of potato and bare soil on G. ellingtonae egg hatch was evaluated; in 2014 and 2015, packages containing cysts in soil were buried under potato or in bare soil at the time of planting and eggs per cyst determined weekly. Across years, a significant reduction in eggs per cysts under potato (>50%) was observed 35 days after planting (DAP) and, at 63 DAP, eggs per cyst were reduced by 76 to 96% compared with initial egg per cyst densities. In bare soil, the maximum reduction in densities of eggs per cyst was 55 to 73%. This annual reduction in egg numbers of G. ellingtonae in bare soil is similar to that reported for G. pallida and G. rostochiensis.

Susceptibility in Viburnum to Phytophthora ramorum.

Phytophthora ramorum, the causal agent of sudden oak death on oak and tanoak and Ramorum blight or Ramorum shoot dieback on ornamentals, is a recently emerged pathogen. Viburnum is a genus of commonly grown ornamental shrubs known to be susceptible to P. ramorum. The entire genus has been placed on the P. ramorum host list. The range of susceptibility of genotypes in the genus is currently not understood. We evaluated whether or not cultivars in the genus Viburnum differ in susceptibility to P. ramorum in controlled, detached leaf inoculations using two isolates belonging to the two clonal lineages found in Oregon. The genus Viburnum shows remarkable differences in susceptibility to infection by P. ramorum. Viburnum genotypes differed significantly in susceptibility to P. ramorum in detached leaf inoculations. V. × burkwoodii was consistently the most susceptible host genotype, followed by V. plicatum 'Mariesii' and V. lentago. Most cultivars evaluated for resistance to P. ramorum were not susceptible or developed only small lesions as determined with a detached leaf assay. Our work only provides information on leaf based resistance, and inferences on epidemic development in whole canopies and under field conditions cannot currently be made.