United States Department of Agriculture – Agricultural Research Service Agricultural Research Service Natural Products Utilization Research Unit National Center for Natural Products Research New Pesticide Modes of Action from Natural Products Stephen O. Duke [email protected]
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United States Department of Agriculture – Agricultural Research Service
Agricultural Research ServiceNatural Products Utilization Research Unit
National Center for
Natural Products Research
New Pesticide Modes of
Action from Natural
Products
Stephen O. Duke
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
United States Department of Agriculture – Agricultural Research Service
Why biopesticides?
• Good source of compounds with novel
molecular targets
• A way of leveraging biopesticide
research
United States Department of Agriculture – Agricultural Research Service
Partial List of Biologicals and Natural Products Curently Used as Seed Treatments. Column1
Column2 PG
R
SAR
Nu
trit
ion
Pla
nt
Hea
lth
Inse
ctic
ide
Bio
-fu
ngi
cid
e
Nem
atic
ide
Bio
-her
bic
ide
Bio
-sti
mu
late
Ino
cula
nt
Syn
ergi
st
Ad
juva
nt:
su
rfac
tan
t
See
d
Soil
Folia
r
Co
rn
Soy
Wh
eat
Can
ola
Alf
alfa
Sorg
hu
m
Co
tto
n
Ric
e
Po
tato
Pea
nu
t
Pu
lses
Suga
r b
eet
Rye
Bar
ley
Pas
ture
/Tu
rf
Orn
amen
tals
Fru
it
Veg
etab
les
Fore
stry
Bacillus .spp. x x x x x x x x x x x x x x x x x x x x x
Bacillus amyloliquefaciens x x x x x x x x x x x x x x x x
Bacillus firmus x x x x x x
Bacillus pumilus x x x x x x x x x
Bacillus subtilis x x x x x x x x x x x x
Saponins of Quillaja saponaria x x x x x x x x x x x x x x x x x x x x
Streptomyces lydicus x x x x x x x x
Streptomycin x x x
Spinosad x x x x x x x x x x x x x x x x x x x x
Chitosan x x x x x x x x x x x x x x x x x x x x x x x x x x x
CPPA x x x x x x x x x x x x x x x x x x x x x x x x x x x x x
Cytokinins x x x x x x x x x x x x x x x x x x x x x x
Gibberellic Acid x x x x x x x x x x x x x x x x x x x x x
From Richard Shaw
United States Department of Agriculture – Agricultural Research Service
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
United States Department of Agriculture – Agricultural Research Service
Pest Management Science 2014, 70, 1169-1185.
United States Department of Agriculture – Agricultural Research Service
• 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
United States Department of Agriculture – Agricultural Research Service
United States Department of Agriculture – Agricultural Research Service
Number of modes of action for commercial
products (from HRAC, FRAC, and IRAC)
Herbicides – 21
Insecticides – 28
Fungicides – 41
United States Department of Agriculture – Agricultural Research Service
Herbicides
United States Department of Agriculture – Agricultural Research Service
Köhler & Triebskorn – 2013 – Science 341: 759
herbicides
fungicides
insecticides
United States Department of Agriculture – Agricultural Research Service
Active ingredient registrations for conventional
herbicides from 1997-2010
Synthetic, 91.9%
Synthetic Natural Derived,
8.1%
Weed Management
United States Department of Agriculture – Agricultural Research Service
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
United States Department of Agriculture – Agricultural Research Service
United States Department of Agriculture – Agricultural Research Service
From: Heap, International Survey of Herbicide Resistant Weeds. Online; http://www.weedscience.org.
Year
1996 1998 2000 2002 2004 2006 2008 2010 2012 2014
Gly
ph
osa
te-r
es
ista
nt
sp
ecie
s
0
5
10
15
20
25
30
Global evolved glyphosate-resistant weed species
United States Department of Agriculture – Agricultural Research Service
United States Department of Agriculture – Agricultural Research Service
New modes of action?
Pest Management Science 2012, 68, 505-512.
United States Department of Agriculture – Agricultural Research Service
Year
1920 1930 1940 1950 1960 1970 1980 1990 2000 2010 2020
Mo
de
s o
f A
ctio
n
0
5
10
15
20
25
Data from: Timmons, 1970; Appleby, 2005, and HRAC
United States Department of Agriculture – Agricultural Research Service
Is there a shortage of good
herbicide target sites?
Natural product research suggests no
United States Department of Agriculture – Agricultural Research Service
Amino acid
synthesisTransaminases
b-cystathionase
EPSP synthase
Glutamine synthetase
Acetolactate synthase
Anthranilate synthase
Asparagine synthetase
Aspartate aminotransferase
Ornithine carbamoyl transferase
1-pyrroline-5-carboxylate reductase
Imidazoleglycerolphosphate dehydratase
PhotosynthesisCF1 ATPase
PSI electron diverters
PSII electron transport
Pyruvate orthophosphate
dikinase
Pigment synthesisHydroxyphenylpyruvate dioxygenase
Protoporphyrinogen oxidase
Tyrosine aminotransferase
Phytoene desaturase
ALA synthase
DOXP
Cell divisionb-tubulin assembly
Cellulose synthesis
Vitamin and hormone synthesisDihydropteroate synthase
Auxin receptors
Lipid synthesisDXP synthase
VLCFA elongase
Ceramide synthase
Enoyl-ACP reductase
Farnesyl PP synthase
Acetyl-CoA carboxylase
Acetyl-CoA transacylase
3-oxoacyl-ACP synthase
Obtusifoliol-14-a-methyl demethylase
7-keto-8-aminopelargonic acid synthase
Gene expression and regulationAdenylosuccinate synthase
Isoleucyl-t-RNA synthasePeptide deformylase
Protein phosphatase
RNA polymerase
AMP deaminase
Membrane functionsH+-ATPase
NADH oxidase
MOASynthetic
Natural
Both synthetic and natural
United States Department of Agriculture – Agricultural Research Service
United States Department of Agriculture – Agricultural Research Service
glufosinate
Target: Glutamine synthetase
United States Department of Agriculture – Agricultural Research Service
Callistemon spp.bottlebrush plant
leptospermone
mesotrione
OO
O O
O
O O NO2
S
O
O
Herbicide inspired by a natural compound
United States Department of Agriculture – Agricultural Research Service
Examples of triketon active ingredient registrations derived
from phytochemicals for conventional herbicides from 1997-
2010
leptospermone
geranylgeranylpyrophosphate
phytoene
ζ-carotene
carotenoid
PQ
Tyrosine 4-hydroxyphenylpyruvate
homogentisate
α-tocopherol
PQH2
Transaminase
HPPD
PSY
PDS
Triketone herbicides
United States Department of Agriculture – Agricultural Research Service
United States Department of Agriculture – Agricultural Research Service
Retention Time (min)
20 25 30 35 50
M C
oun
t
0.0
2.0e+5
4.0e+5
6.0e+5
8.0e+5
1.0e+6
1.2e+6
0
5000
10000
15000
20000
25000
30000
1
2
4
3
Retention Time (min)
20 25 30 35 50
M C
ount
0
1e+6
2e+6
3e+6
4e+6
2000
4000
6000
8000
10000
12000
14000
160001
2 4
3
• 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
Isolation and purification of β-triketones
from Leptospermum scoparium
United States Department of Agriculture – Agricultural Research Service
Leptospermum spp. (tea tree)
Manuka oil is about 40% natural triketones
OO
OHO
Leptospermone
OO
OHO
Isoleptospermone
OO
OHO
Flavesone
OO
OHO
Grandiflorone
United States Department of Agriculture – Agricultural Research Service
Effect of Manuka oil and its components on HPPD activity
Manuka oil
Triketone
Leptospermone
Flavensone
Grandiflorone
Sulcotrione
Inhibitor (g/mL)
0.001 0.01 0.1 1 10 100
HG
A (
nm
ol/m
g p
rote
in/h
)
0
2000
4000
6000
8000
10000
12000
United States Department of Agriculture – Agricultural Research Service
0.5% Agridex 0.5% Agridex + 0.5% manuka oil
Pigweed (Amaranthus retroflexus)
United States Department of Agriculture – Agricultural Research Service
Barnyard grass (Echinocloa crus-galli)
United States Department of Agriculture – Agricultural Research Service
• from Alternaria alternata
• excellent selectivity
• novel molecular target -
CF1 ATPase
Tentoxin
United States Department of Agriculture – Agricultural Research Service
• ca. $200/mg
United States Department of Agriculture – Agricultural Research Service
phosphinothricin
5-methyltryptophanAmino acid synthesis
Ornithine carbamoyl transferase
rhizobitoxine
b-cystathionase
United States Department of Agriculture – Agricultural Research Service
Cytochrome
b6f
H2O
O2
H+
H+
H+
Light
Light
H+OEC
PSII
PQ
PQH2
PC
PSI
H+
H+
NADP+ NADPH
PiADP
ATP
Chloroplaststroma
Thylakoidlumen
ATPase
1
2
45
3
FD
tentoxin
sorgoleone
aurachin A nigericin
Photosynthetic energy transduction
United States Department of Agriculture – Agricultural Research Service
gabaculine
fosmidomycin
leptospermone
Photosynthetic pigment synthesis
United States Department of Agriculture – Agricultural Research Service
Lipid synthesis
thiolactomycinb-ketocyl-ACP synthase
Enoyl-ACP-reductase
United States Department of Agriculture – Agricultural Research Service
juglone
fusicoccin
syringomycin
cercosporin
Plasma membrane functions and integrity
United States Department of Agriculture – Agricultural Research Service
citral
brefeldin A
thaxtomin
Macrostructure synthesis and integrity
United States Department of Agriculture – Agricultural Research Service
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.
United States Department of Agriculture – Agricultural Research Service
Ascaulitoxin aglycone
2,4,7-triamino-5-hydroxy-octandioyl acid
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 non-host species
Nothing is known about the mode of action
Duke et al. 2011. , Pestic. Biochem. Physiol. 100: 41-50.
MW 218
WSSA – Feb. 5, 2014
United States Department of Agriculture – Agricultural Research Service
Insecticides
United States Department of Agriculture – Agricultural Research Service
Pyrethrins or pyrethrum and the pyrethroids
Sodium channel inhibitors
Permethrin
United States Department of Agriculture – Agricultural Research Service
Natural GABA/glutamate-gated chloride channel inhibitors
Streptomyces avermitilis
United States Department of Agriculture – Agricultural Research Service
Emamectin benzoate is semi-synthetic derivative so
avermectins – same mode of action
United States Department of Agriculture – Agricultural Research Service
Spinosad is composed of a mixture of
spinosyns from an Actinomycete – targets
the nicotinic acetylcholine receptor
Spinosyns A and D
United States Department of Agriculture – Agricultural Research Service
Image from Plant Health Progress article:
Spinetoram: How Artificial Intelligence Combined Natural Fermentation with Synthetic Chemistry to Produce a New Spinosyn Insecticide
United States Department of Agriculture – Agricultural Research Service
nicotine
Neonicotinoids – nicotinic acetylcholine
receptor
United States Department of Agriculture – Agricultural Research Service
Natural products as clues to new modes
of action
Ryania speciosaflubendiamide
United States Department of Agriculture – Agricultural Research Service
Rashid et al. J. Econ. Entomol. (2013) 106:2177-82.
Endothall Cantharidin
“Spanish fly”
United States Department of Agriculture – Agricultural Research Service
Decaleside I (a) and II (b)
From roots of Decalepis hamiltonii
Rajashekar et al. Naturwissenschaten (2012) 99: 832-852
Targets tarsal gustatory sites
United States Department of Agriculture – Agricultural Research Service
Fungicides
United States Department of Agriculture – Agricultural Research Service
Kasugamycin
It inhibits protein synthesis
United States Department of Agriculture – Agricultural Research Service
Polyoxin D
Chitin synthesis inhibitor
United States Department of Agriculture – Agricultural Research Service
Strobilurins – 30% of commercial fungicides
Act at Qo site of complex III of mitochondrial
electron transport
Strobilurin A
Azoxystrobin
Fluoxastrobin
Trifloxystrobin
United States Department of Agriculture – Agricultural Research Service
Phenypyrrole fungicides
Act on MAP/histidine kinase in osmotic signal
transduction
Pyrrolnitrin
Fenpiclonil
Fludioxonil
From Pseudomonas sp.
United States Department of Agriculture – Agricultural Research Service
Natural product that could have led to β-tubulin-
binding fungicides like benomyl
griseofulvin
Penicillium griseofulvin
United States Department of Agriculture – Agricultural Research Service
Acividin
From Streptomyces sviceus
A DNA/RNA synthesis inhibitor that could have
been the inspiration for hymexazol fungicide
hymexazol
United States Department of Agriculture – Agricultural Research Service
Pradimicin A
From Actinomadura hibisca
Zilke and Hall, Eur. J. Org. Chem. (2012) 2012:4153-4163
Antifungal through carbohydrate binding
United States Department of Agriculture – Agricultural Research Service
Pest Management Science 2014, 70, 1169-1185.
United States Department of Agriculture – Agricultural Research Service
• 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
United States Department of Agriculture – Agricultural Research Service
Natural products for pest control: an analysis of
their role, value and future – Gerwick & Sparks
Pest Management Science
3 MAR 2014 DOI: 10.1002/ps.3744
http://onlinelibrary.wiley.com/doi/10.1002/ps.3744/full#ps3744-fig-0002
Synthetic
NP insecticide
NP fungicide
NP herbicide
Percentage of known commercial modes of action – (HRAC/IRAC/FRAC)
6% 2%
7%
85%
NP = natural products only
United States Department of Agriculture – Agricultural Research Service
Natural products for pest control: an analysis of
their role, value and future – Gerwick & Sparks
Pest Management Science
3 MAR 2014 DOI: 10.1002/ps.3744
http://onlinelibrary.wiley.com/doi/10.1002/ps.3744/full#ps3744-fig-0002
Synthetic
NP insecticide
NP fungicide
NP herbicide
Percentage of known commercial modes of action - (HRAC/IRAC/FRAC)
67%
16%
11%
6%
NP = natural products + natural product inspired
United States Department of Agriculture – Agricultural Research Service
Natural products for pest control: an analysis of
their role, value and future – Gerwick & Sparks
Pest Management Science
3 MAR 2014 DOI: 10.1002/ps.3744
http://onlinelibrary.wiley.com/doi/10.1002/ps.3744/full#ps3744-fig-0002
Synthetic
NP insecticide
NP fungicide
NP herbcicide
Percentage of known commercial modes of action – (HRAC/IRAC/FRAC)
39%
15%
23%
23%
NP = natural products + natural product inspired + natural product model
United States Department of Agriculture – Agricultural Research Service
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
United States Department of Agriculture – Agricultural Research Service
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