WO2018118768A1 - Utilisation d'acides zaragoziques en tant qu'antifongiques en agriculture - Google Patents

Utilisation d'acides zaragoziques en tant qu'antifongiques en agriculture Download PDF

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Publication number
WO2018118768A1
WO2018118768A1 PCT/US2017/066995 US2017066995W WO2018118768A1 WO 2018118768 A1 WO2018118768 A1 WO 2018118768A1 US 2017066995 W US2017066995 W US 2017066995W WO 2018118768 A1 WO2018118768 A1 WO 2018118768A1
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zaragozic
agricultural product
fungal infection
composition according
acids
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PCT/US2017/066995
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English (en)
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Jon D. Polishook
Daniel P. RING
Sheo B. Singh
James Frederic Walter
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Agrobiologics Llc
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N63/00—Biocides, pest repellants or attractants, or plant growth regulators containing microorganisms, viruses, microbial fungi, animals or substances produced by, or obtained from, microorganisms, viruses, microbial fungi or animals, e.g. enzymes or fermentates
    • A01N63/30—Microbial fungi; Substances produced thereby or obtained therefrom

Definitions

  • the present invention is concerned with the use of the naturally occurring zaragozic acids (ZA's) as agricultural fungicides.
  • the invention is also concerned with compositions comprising one or more zaragozic acids, their preparation, and methods of using such compositions to control agricultural pests including, but not limited to, fungi selected from the group consisting of Boytrytis cinerea, Magnaporthe oryzae, Phytophthora capsici, Alternaria solani, Fusarium oxysporum, Rhizoctonia solani, and Pythium sylvaticum
  • Zaragozic acids comprise a class of natural products discovered at Merck in the early 1990's through in vitro screening in programs to discover novel cholesterol -lowering agents (Bergstrom et al., Proceedings of National Academy of Sciences 1993, 90, 80-84;
  • zaragozic acid A also known as squalestatin 1 (Baxter et al., Journal of Biological Chemistry 1992, 267, 11705-11708; Dawson et al., Journal of Antibiotics 1992, 45, 639-647) is typically the major constituent produced in the fermentation mixtures.
  • Zaragozic acids A B, and C also have antifungal activity (Milligan et al.,
  • Zaragozic acid A or squalestatin- 1 has also been shown to have in vitro antifungal activity against similar mammalian pathogens: Candida sp., Cryptococcus sp., Aspergillus sp., Trichophyton sp.
  • the zaragozic acids, squalestatin 2, and squalestatin 3 all contain a common 4,6,7-trihydroxy-2,8-dioxobicyclo(3.2.1)octane-3,4,5 tricarboxylic acid core but differ in the identity of the two variable side chains attached to the ring structure.
  • compositions, uses, and methods of the present invention are intended to encompass a single zaragozic acid, such as zaragozic acid A, or a mixture of two or more zaragozic acids.
  • zaragozic acids are produced by a number of fungi including Mollisia sp. (Tanimoto et al Journal of Antibiotics 1998, 51, 428-431), Sporormiella intermedia, Leptodontidium elatius, Curvularia lunata, Exserohilum rostratum, Setosphaeria khartoumensis, Drechslera biseptata, Pseudodiplodia sp., Phoma sp., Amauroascus niger, Libertella sp., and Cladosporium cladosporiodes (Bergstrom et al, Annual Review of
  • Plant diseases caused by fungal infection represent a large variety of diseases with significant economic value to farmers, producers and garden keepers. Some of these diseases caused by fungal infection are described in greater detail below.
  • Botrytis cinerea cause diseases in various plants of commercial value, including grapes.
  • Magnaporthe oryzae is a hemibiotrophic fungal pathogen that causes rice (Oryza sativd) blast, the most damaging disease on rice.
  • Alternaria solani is a fungal pathogen that produces a disease in tomato and potato plants called early blight that is extremely destructive to these plants.
  • Septoria tritici blotch (STB) caused by the ascomycete fungus Mycosphaerella graminicola (asexual stage: Septoria tritici), is one of the most important foliar diseases of wheat.
  • Fusarium oxysporum is a pathogenic fungus common in soils around the world, and the cause of fusarium wilt, a deadly vascular wilting syndrome in plants. Fusarium oxysporum comprises over 120 known strains or "special forms" (formae speciales; f. sp.), each of which is specific to a unique plant host in which it causes disease. Collectively, these F.
  • Rhizoctonia solani causes a wide range of commercially significant plant diseases. It is one of the fungi responsible for Brown patch (a turfgrass disease), damping off (e.g., in soybean seedlings), as well as black scurf of potatoes, bare patch of cereals, root rot of sugar beets, belly rot of cucumber, sheath blight of rice, and many other pathogenic conditions.
  • Pythium induced root rot is a common crop disease. When the organism kills newly emerged or emerging seedlings, it is known as darning off and is a very common problem in fields and greenhouses. This disease complex usually involves other pathogens, such as Phytophthora and Rhizoctonia. Pythium wilt is caused by zoospore infection of older plants, leading to biotrophic infections that become necrotrophic in response to colonization/reinfection pressures or environmental stress, leading to minor or severe wilting caused by impeded root functioning. Many Pythium species, along with their close relatives Phytophthora, are plant pathogens of economic importance in agri culture. Pythium spp. tend to be very general and non-selective in their wide range of hosts, while Phytophthora spp. are generally more host-specific.
  • zaragozic acids are useful as agricultural fungicides to treat, prevent, or control fungal infections in agricultural products, such as plants and seeds.
  • zaragozic acids have been found to be effective in treating, preventing, or controlling infections in agricultural products caused by the following fungi: Boytrytis cinerea, Magnaporthe oryzae, Phytophthora capsici, Alternaria solani, Fusarium oxysporum, Rhizoctonia solani, and Pythium sylvaticum.
  • a second aspect of the present invention is concerned with agricultural compositions of one or more zaragozic acids comprising an effective amount of the antifungal compound or compounds and an agriculturally acceptable carrier.
  • Such compositions may additionally comprise one or more excipients selected from the group consisting of (a) a diluent, (b) a dispersing agent, (c) an emulsifying agent, (d) a wetting agent, (e) a surfactant, and (f) a sticking agent.
  • the single zaragozic acid is zaragozic acid A.
  • Zaragozic acids and agricultural compositions of zaragozic acids of the present invention may also be used in combination with one or more other agents useful to treat, prevent, or control agricultural pests in the field.
  • the compositions of the present invention and other active agents may be administered separately or in conjunction.
  • the administration of one element may be prior to, concurrent to, or subsequent to the
  • Examples of other active ingredients that may be administered in combination with the zaragozic acids of the present invention, and either administered separately or in the same agricultural composition, include, but are not limited to:
  • antifungal agents such as Ilicicolin H, aureobasidin A, azoxystrobin and myclobutanil;
  • plant growth regulators such as dikegulac-sodium and trinexapac-ethyl
  • herbicides such as prodiamine and glyphosate
  • insecticides such as bifenthrin and malathion
  • acaricides such as avermectin and kelthane.
  • the agricultural compositions of the present invention may contain about 0.1 to 95 percent by weight of one or more zaragozic acids.
  • compositions of the present invention may be applied using a variety of methodologies, including soil drench, seed treatment, granular and foliar spray. With regard to the treatment of seeds, the compositions may alternatively be applied directly to the seed before planting of the seed or applied to the locus or soil in which the seeds are sown prior to the planting of the seed.
  • the concentration of the zaragozic acid or mixture of zaragozic acids to be applied to the agricultural product is about 0.001 to 1 percent by weight. In a class of this method the concentration of the zaragozic acid or acids to be applied to the agricultural product is about 0.001 to 0.01 percent by weight.
  • Another aspect of the present invention relates to the total amount of the zaragozic acid or mixture of zaragozic acids to be applied per area of the field.
  • about 2 to about 1000 grams of the zaragozic acid or mixture of zaragozic acids are to be applied per acre.
  • about 5 to 500 grams of the zaragozic acid or mixture of zaragozic acids are to be applied per acre.
  • about 0.025 kilograms to about 5 kilograms of the zaragozic acid or mixture of zaragozic acids are to be applied per hectare.
  • about 0.05 kilograms to about 1 kilogram of the zaragozic acid or mixture of zaragozic acids are to be applied per hectare.
  • Another aspect of the present invention relates to the use of a zaragozic acid or mixture of zaragozic acids and the compositions of the present invention to treat, control, or prevent fungal infections on an agricultural product.
  • the present invention also relates to a food, feed, or agricultural product treated with a composition of the present invention.
  • the present invention also relates to a process for the treatment of an agricultural product which comprises applying a composition of the present invention to such agricultural product or plant.
  • the present invention also relates to the use of a fermentation broth derived from strains selected from the group consisting of Pseudodiploidia sp., Sporormiella intermedia, Mollisia sp., Curvularia lunata, Exserohilum rostratum, Setophaeria khartoumensis, Drechslera biseptata, Phoma sp., Amour oascus niger, Libertella sp., Cladosporium cladosporiodes, and Leptodontidium elatius as a live cell or cell suspension to treat, control, or prevent a fungal infection on an agricultural product.
  • strains selected from the group consisting of Pseudodiploidia sp., Sporormiella intermedia, Mollisia sp., Curvularia lunata, Exserohilum rostratum, Setophaeria khartoumensis
  • Such fermentation broths contain one or more of the zaragozic acids, which need not be isolated, purified, and re-formulated for use as agricultural fungicides.
  • the fermentation broth is derived from strains of Pseudodiploidia sp.
  • the present invention also relates to the use of an organic solvent extract of a fermentation broth derived from strains of Sporormiella intermedia, Mollisia sp., Curvularia lunata, Exserohilum rostratum, Setophaeria khartoumensis, Drechslera biseptata, Phoma sp., Amauroascus niger, Libertella sp., Cladosporium cladosporiodes, or Leptodontidium elatius to treat, control, or prevent a fungal infection on an agricultural product.
  • the present invention is concerned with the use of one zaragozic acid or a mixture of two or more zaragozic acids to control the growth of agricultural pests including, but not limited to, Boytrytis cinerea, Magnaporthe oryzae, Phytophthora capsici, Alternaria solani, Fusarium oxysporum, Rhizoctonia solani, and Pythium sylvaticum.
  • the zaragozic acid is zaragozic acid A.
  • Zaragozic acids can be used to control a variety of plant diseases and can be applied in a variety of methodologies, including soil drench, seed treatment, granular and foliar spray. It can be readily formulated into a variety of compositions, including, but not limited to, emulsifiable concentrates, inverse emulsions, microemulsions, dispersible granules, wettable powders, dusts, and granules.
  • Zaragozic acids offers several advantages over existing synthetic fungicides. Since they are derived from natural sources, they already occur in the environment and biological processes to degrade them are already present in the environment. Unlike many conventional fungicides, the zaragozic acids do not contain any heavy metals or halogens and therefore is totally biologically degradable. Moreover, zaragozic acids have a different mechanism of action from existing commercial fungicides and therefore can be used to reduce fungicide resistance found in certain plant diseases.
  • agricultural product as used herein is to be understood in a very broad sense and includes, but is not limited to, cereals, e.g., wheat, barley, rye, oats, rice, sorghum, and the like; beets, e.g. sugar beet and fodder beet; pome and stone fruit and berries, e.g. apples, pears, plums, apricots, peaches, almonds, cherries, strawberries, raspberries and blackberries; leguminous plants, e.g. beans, lentils, peas, and soybeans; oleaginous plants, e.g.
  • rape mustard, poppy, olive, sunflower, coconut, castor-oil plant, cocoa, and ground-nuts
  • cucurbitaceae e.g. pumpkins, gherkins, melons, cucumbers, squashes, and aubergines
  • fibrous plants e.g. cotton, flax, hemp, and jute
  • citrus fruit e.g. oranges, lemons, grapefruits, mandarins, and limes
  • tropical fruit e.g. papayas, passion fruit, mangos, carambolas, pineapples, bananas, and kiwis
  • vegetables e.g. spinach, lettuce, asparagus
  • brassicaceae such as cabbage and turnips, carrots, onions, tomatoes, potatoes, seed potatoes, hot and sweet peppers
  • laurel-like plants e.g. avocado, cinnamon, camphor tree
  • products such as maize, tobacco, nuts, coffee, sugarcane, tea, grapevines, hops, rubber plants, as well as ornamental plants, e.g.
  • cut flowers roses, tulips, lilies, Narcissus, crocuses, hyacinths, dahlias, Gerbia, carnations, fuchsias, chrysanthemums, and flower bulbs, shrubs, deciduous trees and evergreen trees such as conifers, plants and trees in greenhouses. It includes, but is not limited to, plants and their parts, fruits, seeds, cuttings, cultivars, grafts, bulbs, tubers, root-tubers, rootstocks, cut flowers and vegetables.
  • EXAMPLE 1 Suspensions of mycelial fragments or conidia of a fungal species, prepared either freshly from liquid cultures of the fungus or from cryogenic storage, were directly mixed into nutrient broth. Dilutions of zaragozic acid A (from 0.03 to 180 ppm) were diluted with 0.025% Tween 20, and 10 ⁇ . of this solution was pipetted into a microtitre plate (96-well format). The nutrient broth containing the fungal spores/mycelia fragments was then added to give a final concentration of zaragozic acid A. The test plates were incubated in the dark at 24°C and 96% relative humidity.
  • the zaragozic acids used in the present invention can be produced by the procedure described in U.S. Patent No. 5,284,758, the contents of which are hereby incorprated by reference in their entirety.
  • Pseudodiplodia sp. culture MF5767 is inoculated into KF seed medium (corn steep liquor 5 g/L, tomato paste 40 g/L, oat flour 10 g/L, cerelose 10 g/L, trace elements: (FeS0 4 .7H 2 0 1 g/L, MnS0 4 .4H 2 0 1 g/L, CuCl 2 .2H 2 0 0.025 g/L, CaCl 2 .2H 2 0 0.1 g/L, H 3 BO 3 0.056 g/L, (NH 4 ) 6 M0 7 0 24 .4H 2 0 0.019 g/L, ZnS0 4 .7H 2 0 0.2 g/L dissolved in 1 L
  • the KF seed flask is incubated for 69 hours at 25° C, 220 rpm, and 85% humidity. At the end of this incubation, 2.0 mL aliquots are aseptically transferred to each of 6 CYG 40 production medium (corn meal 50 g/L, yeast extract 1 g/L, glucose 40 g/L) flasks. These production flasks are then incubated at 25° C, 220 rpm on a gyrotory shaker, 85% humidity, with a fermentation cycle of 14 days.
  • 6 CYG 40 production medium corn meal 50 g/L, yeast extract 1 g/L, glucose 40 g/L
  • Production flasks are harvested as follows: the contents of the flasks are homogenized for 60 seconds using a handheld Biospec homogenizer (Bartlesville, Okla.) and then 45 mL of 100% methanol is added to each of three production flasks; 50 mL of methyl ethyl ketone (MEK) is added to each of the three remaining flasks. All solvent treated production flasks are then placed onto a gyrotory shaker at 220 rpm for 30 minutes. After shaking, the contents of the solvent treated flasks are pooled into two separate 500-mL Erlenmeyer flasks: (1) a methanol extracted preparation and (2) a MEK extracted preparation.
  • the zaragozic acids can be purified from these extracts as described in US Patent No. 5,284,758.
  • the predominant ZA in this mixture is zaragozic acid A.
  • the fermentation broth from producer strains can be processed in several ways depending on the utility.
  • the fermentation broth is separated and extracted with methyl ethyl ketone, ethanol, methanol, acetone or ethyl acetate.
  • the extract is concentrated and the zaragozic acid or acids are purified as described in US Patent No. 5,284,758.
  • the fermentation broth is lyophilized to remove water affording a dry powder.
  • the cells in the fermentation broth are broken if necessary by addition of an organic solvent, such as methanol, ethanol, acetone, and the like, and then evaporated to dryness to afford a powder.
  • the fermentation broth obtained directly or after breaking the cells with solvent is sprayed onto the plant by foliar treatment, mixed with seeds, or used as a soil inoculant.
  • broth powders generated using either of the two methods is mixed with appropriate agent(s) and sprayed by foliar treatment, mixed with seeds, or used as a soil inoculant.
  • Phoma sp. C2932 can be cultivated and compounds purified as described by Dawson et al. in Journal of Antibiotics 1992, 45, 639-647. Phoma sp. C2932 is maintained on oatmeal agar plates. Liquid cultures are inoculated with 6 mm agar plugs taken directly from plates, or previously stored in distilled water at room temperature. Vegetative seed growth in broth can also be used as an inoculum source and stored frozen at -20 °C.
  • Seed cultures are inoculated with two agar plugs (or vegetative culture) added to a 250-ml Erlenmeyer flask containing 50 mL of a medium of the following composition: Peptone (10 g), malt extract (21 g), glycerol (40 g), Junlon PW110 (1 g) in 1 L of distilled water.
  • the pH of the medium is adjusted to 6.5 by the addition of aqueous NaOH before autoclaving.
  • the flasks of inoculated seed medium are incubated at 25°C on an orbital shaker platform, rotating at 250 rpm with a 50-mm throw, for 5 days.
  • the contents of seed flasks are pooled and homogenized in a sterile Waring blender and used at 3% to inoculate 50 mL aliquots of fermentation medium in 250-mL
  • the fermentation medium contains glycerol (50 g), soybean oil (30 g) and cottonseed flour (10 g) in 1 L of distilled water.
  • the pH of the medium is about 6.1 to 6.3 before autoclaving.
  • the flasks are incubated with shaking (as above) for 8 days.
  • the fermentation broth from producer strains can be processed in several ways depending on the utility.
  • the fermentation broth is separated and extracted with methyl ethyl ketone, ethanol, methanol, acetone or ethyl acetate.
  • the extract is concentrated and the mixture of zaragozic acids (predominantly zaragozic acid A) is used as is, or the individual zaragozic acids (squalestatins) in the mixture are purified as described in Dawson et al., Journal of Antibiotics 1992, 45, 639-647.
  • the fermentation broth is lyophilized affording a dry powder.
  • the cells in the fermentation broth are broken if necessary by addition of an organic solvent, such as methanol, ethanol, acetone, and the like, and then evaporated to dryness to afford a powder.
  • the fermentation broth obtained directly or after breaking the cells with solvent is sprayed onto the plant by foliar treatment, mixed with seeds, or used as a soil inoculant.
  • broth powders generated using either of the two methods can be mixed with appropriate agent(s) and sprayed by foliar treatment, mixed with seeds, or used as a soil inoculant.
  • the zaragozic acids used in the present invention can also be obtained from producing organisms as described by Bergstrom et al. in Proceedings of National Academy of Sciences 1993, 90, 80-84 and Dufresne et al. in Journal of Natural Products 1993, 56, 1923- 1929.
  • the fungal slants composed of 4 g of yeast extract, 10 g of malt extract, 4 g of dextrose, and 20 g of agar per liter at pH 7.0.
  • the zaragozic acids are produced in a two-tiered fermentation process consisting of mycelial growth and development in medium A and product formation in medium C.
  • Medium C contains 5 g of malt extract, 1 g of peptone, 15 g of dextrose, 1 g of KH2PO4, and 0.5 g of MgSC"4 7I3 ⁇ 40 per liter. Fermentations consists of mycelial growth in medium A for 72 hr at 250 °C with agitation, followed by inoculation (5- 10%) of medium C. Maximum yields are obtained from 14-day agitated fermentations at 250 °C.
  • the fermentation broth from producer strains can be processed in several ways depending on the utility.
  • the fermentation broth is separated and extracted with methyl ethyl ketone, ethanol, methanol, acetone or ethyl acetate.
  • the extract is concentrated and the mixture of zaragozic acids is used as is, or the individual zaragozic acids in the mixture are purified as described in Berstrom et al., in Proceedings of National Academy of Sciences 1993, 90, 80-84 or Dufresne et al., in Journal of Natural Products 1993, 56, 1923-1929.
  • the fermentation broth is lyophilized affording a dry powder.
  • the cells in the fermentation broth are broken if necessary by addition of an organic solvent, such as methanol, ethanol, acetone, and the like, and then evaporated to dryness to afford a powder.
  • the fermentation broth obtained directly or after breaking the cells with solvent is sprayed onto the plant by foliar treatment, mixed with seeds, or used as a soil inoculant.
  • broth powders generated using either of the two methods can be mixed with appropriate agent(s) and sprayed by foliar treatment, mixed with seeds, or used as a soil inoculant.

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  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Wood Science & Technology (AREA)
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  • Plant Pathology (AREA)
  • Pest Control & Pesticides (AREA)
  • Agronomy & Crop Science (AREA)
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Abstract

La présente invention concerne l'utilisation d'acides zaragoziques d'origine naturelle en tant que fongicides agricoles, des compositions comprenant un ou plusieurs acides zaragoziques et l'utilisation de telles compositions pour traiter, lutter contre ou prévenir une infection fongique dans des produits agricoles, en particulier, lorsque les champignons sont choisis dans le groupe constitué par Boytrytis cinerea, Magnaporthe oryzae, Phytophthora capsici, Alternaria solani, Fusarium oxysporum, Rhizoctonia solani et Pythium sylvaticum.
PCT/US2017/066995 2016-12-19 2017-12-18 Utilisation d'acides zaragoziques en tant qu'antifongiques en agriculture WO2018118768A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5055487A (en) * 1990-03-21 1991-10-08 Merck & Co., Inc. Novel anti-fungal compounds
US5284758A (en) * 1992-08-14 1994-02-08 Merck & Co., Inc. Process for forming cholesterol lowering compound using pseudodiplodia sp.
US5430055A (en) * 1994-04-08 1995-07-04 Pfizer Inc. Inhibitor of squalene synthase
WO2011031964A2 (fr) * 2009-09-10 2011-03-17 President And Fellows Of Harvard College Inhibiteurs de la formation de biofilm
WO2016151293A1 (fr) * 2015-03-25 2016-09-29 The University Of Nottingham Composition/traitement antifongique.

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5055487A (en) * 1990-03-21 1991-10-08 Merck & Co., Inc. Novel anti-fungal compounds
US5284758A (en) * 1992-08-14 1994-02-08 Merck & Co., Inc. Process for forming cholesterol lowering compound using pseudodiplodia sp.
US5430055A (en) * 1994-04-08 1995-07-04 Pfizer Inc. Inhibitor of squalene synthase
WO2011031964A2 (fr) * 2009-09-10 2011-03-17 President And Fellows Of Harvard College Inhibiteurs de la formation de biofilm
WO2016151293A1 (fr) * 2015-03-25 2016-09-29 The University Of Nottingham Composition/traitement antifongique.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BERGSTROM ET AL.: "DISCOVERY, BIOSYNTHESIS, AND MECHANISM OF ACTION OF THE ZARAGOZIC ACIDS: Potent Inhibitors of Squalene Synthase", ANNU. REV. MICROBIOL., vol. 49, 1995, pages 607 - 39, XP009049539, DOI: doi:10.1146/annurev.mi.49.100195.003135 *

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