Source: DIVERGENCE, INC. submitted to
A NEW SAFER CLASS OF AGRICULTURAL NEMATICIDES TARGETING A SPECIFIC GENE
Sponsoring Institution
National Institute of Food and Agriculture
Project Status
TERMINATED
Funding Source
Reporting Frequency
Annual
Accession No.
0199712
Grant No.
2004-33610-14352
Project No.
MOK-2004-00070
Proposal No.
2004-00070
Multistate No.
(N/A)
Program Code
8.2
Project Start Date
May 15, 2004
Project End Date
Dec 31, 2005
Grant Year
2004
Project Director
Shortt, B. J.
Recipient Organization
DIVERGENCE, INC.
893 NORTH WARSON RD.
ST. LOUIS,MO 63141
Performing Department
(N/A)
Non Technical Summary
Plant parasitic nematodes are among the most important pests of crops in the United States. The USDA's Committee on National Needs and Priorities in Nematology estimated the value of plant damage by nematodes in the U.S. at $7-9 billion annually. Chemical control of nematodes has proven to be effective; however most nematicides have toxicological or environmental concerns and many are under regulatory pressure. The goal of this research is the development of novel, safe and effective nematicidal agents for use against plant-parasitic nematodes. An Active Mixture with specificity and activity against plant parasitic nematodes has been selected from a new class of safer chemistry. Formulation technology will be used to optimize bioavailability of the compound in soil achieving at least a five-fold improvement in potency. Performance in soil and spectrum of activity will be characterized and this information will be used to design a field evaluation program for Phase II in key crops such as tomato, potato, tobacco, cotton, soybean, and turf. Positive results in Phase II will lead to the rapid commercialization of a new nematicide for U.S. growers.
Animal Health Component
(N/A)
Research Effort Categories
Basic
(N/A)
Applied
100%
Developmental
(N/A)
Classification

Knowledge Area (KA)Subject of Investigation (SOI)Field of Science (FOS)Percent
2121460112010%
2123130112030%
2123130115030%
2125220200030%
Goals / Objectives
We have used the Caenorhabditis elegans genome sequence together with parasitic nematode expressed sequence tags (ESTs) and proprietary bioinformatics to identify genes that are essential in nematodes but are absent in mammals. Using a specific gene product as a target, we have identified a class of inhibitory compounds with good in vitro activity against several plant parasitic nematodes and with a favorable preliminary toxicology profile. Potted plant tests using Meloidogyne incognita on tomato have confirmed the potential of these compounds for use as agricultural nematicides. The Phase I research will utilize formulation technology to optimize the compounds performance in soil by improving their bioavailability and stability. The utility of the compounds for the specific needs of U.S. growers will be determined by characterizing their soil performance and spectrum of activity across multiple crops and nematode species. The specific objectives of this Phase I proposal are (1) to develop a formulation that optimizes bioavailability and potency of the Active Mixture in soil, and (2) to determine the spectrum of activity of the best formulations on key species of plant-parasitic nematodes. We expect to develop a formulation that is active at 10 ppm or less, with demonstrable activity across a spectrum of plant-parasitic nematodes.
Project Methods
The compounds under investigation are in general lipophilic and have poor water solubility, limiting distribution and bioavailability in the soil. These and other performance characteristics may be significantly improved by the design of an emulsifiable formulation that is optimized for several characteristics. A series of surfactants and solvents will be altered in a controlled fashion for evaluation of positive impact on efficacy. Using a column-flush assay system, candidate formulations will be tested for increased efficacy against Meloidogyne incognita J2 larvae. A wide variety of formulations can be screened efficiently with this method. Confirmation and further characterization of promising formulations will be done in the greenhouse on potted tomato plants in sand infested with Meloidogyne incognita. Soil persistence and efficacy will also be determined in a potted root knot assay utilizing sand or sand containing 10% microbially active soil. Fenamiphos will be used as the benchmark for soil longevity. Experiments to demonstrate the utility of specific formulations will be undertaken, using parasitic nematodes representing sedentary endoparasites (Heterodera glycines), migratory endoparasites (Pratylenchus scribneri), ectoparasites (Belonolaimus longicaudatus), and foliar nematodes (Aphelencoides spp.). Potted plant tests will be carried out on soybean, corn, turf and ornamentals, respectively. This research represent s the next stages of a rational approach to research and development of what may become the first new class of commercializable nematicidal reagents in more than twenty years.

Progress 05/15/04 to 12/31/05

Outputs
Plant parasitic nematodes are among the most important pests of crops in the United States, causing an estimated $7-9 billion in damages annually. Although chemical control of nematodes has proven effective, the existing nematicides have toxicological, environmental or regulatory issues that preclude their wide-spread use. Our goal is to develop novel nematicidal products that are effective and safe. As Phase I work began, hydroxyelaidic acid methyl ester (DC7651) was the most active representative of a series of promising nematicidal fatty acid derived compounds. Greenhouse evaluations previously demonstrated that high lipophilicity and short longevity of action associated with this compound in soil would negatively impact field performance. We report here on the results of two research approaches to improve the bioavailability and potency of this and related chemistries. In Objective 1a we sought to develop a formulation that optimizes potency and bioavailability in soil. Formulations were prepared using the product of our manufacturing process, containing 70% hydroxyelaidic acid methyl ester. Numerous experimental emulsifiable concentrates (EC) were evaluated in vitro to estimate bioavailability. Several of these formulations provided significantly enhanced activity in this assay and were advanced to greenhouse evaluations with root knot nematode (Meloidogyne sp.). We evaluated 92 EC formulations and were able to successfully improve the efficacy of the DC7651 mixture. In Objective 1b we synthesized and evaluated novel related molecules. Excellent improvements in potency have been achieved using new analogs based on the starting fatty acid backbone. Analogs DC1717 and DC7700 are 5-10 fold more potent than DC7651 and are important new leads for greenhouse and potentially field evaluation. We plan also to pursue additional syntheses around these structures to further enhance potency. In Objective 2, the spectrum of activity of selected chemicals and formulations was assessed. Efficacy of DC7651 has been demonstrated against most of the major classes of plant pathogenic nematodes including root knot (Meloidogyne sp.), cyst (Heterodera sp.), lesion (Pratylenchus sp.), sting (Belonolaimus sp.), and lance (Hoplolaimus sp.). This spectrum of activity suggests excellent potential as a broad spectrum agricultural nematicide. The long term goal of this research is to develop and market novel nematicides with high efficacy and improved safety profiles. The results of this Phase I study are highly encouraging in this regard. Important information about the lead compounds and potential formulations have been successfully addressed. In Phase II research, we plan to further develop the lead chemistry from this Phase I project towards eventual (Phase III) product development.

Impacts
The development of safe and effective strategies for combatting agronomically important nematode pests is expected to have a significant positive impact on agricultural production. The chemistries and formulations in development through this research are intended to improve upon current nematicidal products, many of which suffer from disadvantageous toxicological, environmental, or regulatory profiles.

Publications

  • McCarter, James P. 2004. Genomic filtering: an approach to discovering novel antiparasitics. Trends Parasitol. 20(10):462-468.