New Pesticide Modes of Action from Natural Products

Transcription

Agricultural Research Service
Natural Products Utilization Research Unit
New Pesticide Modes of
Action from Natural
Products
National Center for
Natural Products Research
Stephen O. Duke
[email protected]
United States Department of Agriculture – Agricultural Research Service
Why new pesticide target sites?
• Pesticide resistance management
• More toxicologicaly benign pesticides
• In some cases, more specificity
Why biopesticides?
• Good source of compounds with novel
molecular targets
• A way of leveraging biopesticide
research
From Richard Shaw
Partial List of Biologicals and Natural Products Curently Used as Seed Treatments.
Bacillus .spp.
x
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Bacillus amyloliquefaciens
x
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Bacillus subtilis
x
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Gibberellic Acid
x
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x
Forestry
Vegetables
Fruit
Ornamentals
Pasture/Turf
Rye
Barley
Pulses
Sugar beet
Peanut
Potato
Rice
x
Streptomycin
x
Cotton
x
x
Cytokinins
Alfalfa
x
x
x
Sorghum
x
x
x
Canola
x
x
x
Soy
x
Streptomyces lydicus
CPPA
x
Wheat
x
x
Chitosan
x
Corn
x
Saponins of Quillaja saponaria
Spinosad
Foliar
Soil
x
x
Bacillus pumilus
Seed
Adjuvant: surfactant
Synergist
Inoculant
x
x
Bacillus firmus
Bio-stimulate
Bio-herbicide
Nematicide
Bio-fungicide
Insecticide
Plant Health
Nutrition
Column2
SAR
PGR
Column1
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New active ingredient registrations for
conventional pesticides from 1997 to
2010, organized by source.
Charles L. Cantrell; Franck E. Dayan;
Stephen O. Duke; J. Nat. Prod. 2012, 75,
1231-1242.
DOI: 10.1021/np300024u
Copyright © 2012
Pest Management Science 2014, 70, 1169-1185.
• Natural compounds used directly –
biochemical biopesticides
• Natural product-inspired synthetic
pesticides
• Synthetic pesticides that could have
been inspired by natural product
mode of action and/or structure
Number of modes of action for commercial
products (from HRAC, FRAC, and IRAC)
 Herbicides
– 21
 Insecticides
 Fungicides
– 28
– 41
Herbicides
Köhler & Triebskorn – 2013 – Science 341: 759
herbicides
fungicides
insecticides
Active ingredient registrations for conventional
herbicides from 1997-2010
Synthetic
Natural
Derived,
8.1%
Synthetic,
91.9%
Weed Management
Share of total herbicide quantity use in the US.
Pest Management Science
Volume 69, Issue 9, pages 1001-1025, 6 JUN 2013 DOI: 10.1002/ps.3529
http://onlinelibrary.wiley.com/doi/10.1002/ps.3529/full#ps3529-fig-0007
Global evolved glyphosate-resistant weed species
Glyphosate-resistant species
30
25
20
15
10
5
0
1996
1998
2000
2002
2004
2006
2008
2010
2012
2014
Year
From: Heap, International Survey of Herbicide Resistant Weeds. Online; http://www.weedscience.org.
New modes of action?
Data from: Timmons, 1970; Appleby, 2005, and HRAC
25
Modes of Action
20
15
10
5
0
1920
1930
1940
1950
1960
1970
1980
1990
2000
2010
2020
Year
Is there a shortage of good
herbicide target sites?

Natural product research suggests no
Pigment synthesis
Hydroxyphenylpyruvate dioxygenase
Protoporphyrinogen oxidase
Tyrosine aminotransferase
Phytoene desaturase
ALA synthase
DOXP
Vitamin and hormone synthesis
Dihydropteroate synthase
Auxin receptors
Gene expression and regulation
Adenylosuccinate synthase
Isoleucyl-t-RNA synthase
Peptide deformylase
Protein phosphatase
Membrane functions
RNA polymerase
AMP deaminase
H+-ATPase
NADH oxidase
Cell division
b-tubulin assembly
Cellulose synthesis
Amino acid
synthesis
Photosynthesis
MOA
Synthetic
CF1 ATPase
PSI electron diverters
PSII electron transport
Pyruvate orthophosphate
dikinase
Transaminases
Lipid synthesis
Natural
b-cystathionase
DXP synthase
EPSP synthase
VLCFA elongase
Both synthetic and natural
Glutamine synthetase
Ceramide synthase
Acetolactate synthase
Enoyl-ACP reductase
Anthranilate synthase
Farnesyl PP synthase
Asparagine synthetase
Acetyl-CoA carboxylase
Aspartate aminotransferase
Acetyl-CoA transacylase
Ornithine carbamoyl transferase
3-oxoacyl-ACP synthase
1-pyrroline-5-carboxylate
reductase
United States
Department of Agriculture Obtusifoliol-14-a-methyl
– Agricultural Researchdemethylase
Service
Imidazoleglycerolphosphate dehydratase
7-keto-8-aminopelargonic acid synthase
Target: Glutamine synthetase
glufosinate
Herbicide inspired by a natural compound
O
O
NO2
O
O
mesotrione
Callistemon spp.
O
S
O
O
bottlebrush plant
O
O
leptospermone
Examples of triketon active ingredient registrations derived
from phytochemicals for conventional herbicides from 19972010
leptospermone
Triketone
herbicides
Tyrosine
4-hydroxyphenylpyruvate
Transaminase
HPPD
geranylgeranyl
pyrophosphate
homogentisate
PSY
phytoene
PQ
PDS
ζ-carotene
carotenoid
PQH2
α-tocopherol
Isolation and purification of β-triketones
1.2e+6
30000
1
4e+6
16000
1.0e+6
25000
14000
12000
8.0e+5
3e+6
M
Count
M Count
• Manuka oil was dissolved in
Et2O
• 99.4% of the triketones were
extracted by liquid phase
partitioning
• It contained 72.9%
leptospermone, 18.4%
isoleptospermone, 7.1%
flavensone and <1%
grandiflorone
20000
1
10000
6.0e+5
4
4
2e+6
2
4.0e+5
33
1e+6
2.0e+5
15000
8000
10000
6000
2
5000
4000
0.0
2000
0
0
20
20
25
25
30
30
35
35
50
50
Retention Time (min)
Retention Time (min)
from Leptospermum scoparium
Leptospermum spp. (tea tree)
Manuka oil is about 40% natural triketones
O
O
O
OH
O
O
O
O
OH
Flavesone
OH
Isoleptospermone
Leptospermone
O
O
O
O
O
OH
Grandiflorone
HGA (nmol/mg protein/h)
Effect of Manuka oil and its components on HPPD activity
12000
10000
Manuka oil
Triketone
Leptospermone
Flavensone
Grandiflorone
Sulcotrione
8000
6000
4000
2000
0
0.001 0.01
0.1
1
10
100
Inhibitor (g/mL)
Pigweed (Amaranthus retroflexus)
0.5% Agridex
0.5% Agridex + 0.5% manuka oil
Barnyard grass (Echinocloa crus-galli)
• from Alternaria alternata
• excellent selectivity
• novel molecular target CF1 ATPase
Tentoxin
• ca. $200/mg
Amino acid synthesis
5-methyltryptophan
rhizobitoxine
phosphinothricin
b-cystathionase
Ornithine carbamoyl transferase
Chloroplast
stroma
H+
H+
NADPH
NADP+
Pi
Light
ADP
ATP
Light sorgoleone
FD
H+
1
PSI
Cytochrome
b6f
PQ
PQH2
PSII
2
H2O
ATPase
PC
4
H+
OEC
aurachin A
3
H+
O2
nigericin
Thylakoid
lumen
H+
5
tentoxin
Photosynthetic energy transduction
fosmidomycin
gabaculine
leptospermone
Photosynthetic pigment synthesis
b-ketocyl-ACP synthase
thiolactomycin
Enoyl-ACP-reductase
Lipid synthesis
Plasma membrane functions and integrity
juglone
fusicoccin
syringomycin
cercosporin
Macrostructure synthesis and integrity
thaxtomin
citral
brefeldin A
See: Dayan, F.E. and S.O. Duke. 2014. Natural
compounds as next generation herbicides. Plant
Physiology 166: 1090-1105
DOI:10.1104/pp.114.239061.
Ascaulitoxin aglycone
2,4,7-triamino-5-hydroxy-octandioyl acid






MW 218
From Ascochyta caulina, a mycoherbide for
lambsquarters (Evidente et al., 1998)
Occurs as both an N-glucoside and an aglycone
Highly potent phytotoxin against host and nonhost species
Nothing is known about the mode of action
Duke et al. 2011. , Pestic. Biochem. Physiol. 100:
41-50.
WSSA – Feb. 5, 2014
Insecticides
Pyrethrins or pyrethrum and the pyrethroids
Sodium channel inhibitors
Permethrin
Natural GABA/glutamate-gated chloride channel inhibitors
Streptomyces avermitilis
Emamectin benzoate is semi-synthetic derivative so
avermectins – same mode of action
Spinosad is composed of a mixture of
spinosyns from an Actinomycete – targets
the nicotinic acetylcholine receptor
Spinosyns A and D
Image from Plant Health Progress article:
Spinetoram: How Artificial Intelligence Combined Natural Fermentation with Synthetic Chemistry to Produce a New Spinosyn Insecticide
Neonicotinoids – nicotinic acetylcholine
receptor
nicotine
Natural products as clues to new modes
of action
flubendiamide
Ryania speciosa
Endothall
Cantharidin
“Spanish fly”
Rashid et al. J. Econ. Entomol. (2013) 106:2177-82.
Decaleside I (a) and II (b)
From roots of Decalepis hamiltonii
Rajashekar et al. Naturwissenschaten (2012) 99: 832-852
Targets tarsal gustatory sites
Fungicides
Kasugamycin
It inhibits protein synthesis
Polyoxin D
Chitin synthesis inhibitor
Strobilurins – 30% of commercial fungicides
Act at Qo site of complex III of mitochondrial
electron transport
Azoxystrobin
Trifloxystrobin
Strobilurin A
Fluoxastrobin
Phenypyrrole fungicides
Act on MAP/histidine kinase in osmotic signal
transduction
From Pseudomonas sp.
Fenpiclonil
Pyrrolnitrin
Fludioxonil
Natural product that could have led to β-tubulinbinding fungicides like benomyl
griseofulvin
Penicillium griseofulvin
A DNA/RNA synthesis inhibitor that could have
been the inspiration for hymexazol fungicide
Acividin
From Streptomyces sviceus
hymexazol
Antifungal through carbohydrate binding
Pradimicin A
From Actinomadura hibisca
Zilke and Hall, Eur. J. Org. Chem. (2012) 2012:4153-4163
• Natural compounds used directly –
biochemical biopesticides
• Natural product-inspired synthetic
pesticides
• Synthetic pesticides that could have
been inspired by natural product
mode of action and/or structure
Percentage of known commercial modes of action – (HRAC/IRAC/FRAC)
6% 2%
7%
Synthetic
NP insecticide
NP fungicide
NP herbicide
85%
NP = natural products only
Natural products for pest control: an analysis of
their role, value and future – Gerwick & Sparks
3 MAR 2014 DOI: 10.1002/ps.3744
Percentage of known commercial modes of action - (HRAC/IRAC/FRAC)
6%
11%
Synthetic
NP insecticide
16%
NP fungicide
67%
NP herbicide
NP = natural products + natural product inspired
3 MAR 2014 DOI: 10.1002/ps.3744
Percentage of known commercial modes of action – (HRAC/IRAC/FRAC)
15%
Synthetic
39%
NP insecticide
23%
NP fungicide
NP herbcicide
23%
NP = natural products + natural product inspired + natural product model
3 MAR 2014 DOI: 10.1002/ps.3744
Some parting thoughts

Natural compounds are still excellent sources of novel
pesticide chemistries with new target sites

Natural compounds can still inspire new pesticides
chemistries with old or new target sites

Natural compounds can lead to discovery of effective
target sites for in vitro screening of effective inhibitors –
both natural compound structure inspired and inhibitors
with very different structures

New Pesticide Modes of Action from Natural Products

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