herbicides state of the art. ii. achievements …...2014/08/07 · isoxaflutole (figure 3) was also...
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Herbicides state of the art. II. Achievements
Hansjoerg Kraehmer
Kantstrasse 20, D-65719 Hofheim Germany
+49 6192 296560
Plant Physiology Preview. Published on August 7, 2014, as DOI:10.1104/pp.114.241992
Copyright 2014 by the American Society of Plant Biologists
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Herbicides as weed control agents – state of the art. II. Recent achievements
Hansjoerg Kraehmer*, Andreas van Almsick, Roland Beffa ,Hansjoerg Dietrich, Peter Eckes, Erwin Hacker, Ruediger Hain, Harry John Strek, Hermann Stuebler, Lothar Willms
Bayer CropScience AG, Industriepark Hoechst, Building H 872, D-65926 Frankfurt am Main
Herbicide discovery has faced significant challenges over the past few decades and weed control innovations are urgently required.
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ABSTRACT
In response to changing market dynamics, the discovery of new herbicides has significantly declined over the past few decades and has only seen a modest upsurge in recent years. Nevertheless the few introductions have proven to be interesting and have brought useful innovation to the market. In addition, HT (herbicide tolerant) or HR (herbicide resistant) crop technologies have also allowed the use of existing non-selective herbicides to be extended into crops. An increasing and now major challenge is being posed by the inexorable increase in biotypes of weeds that are resistant to herbicides. This problem is now at a level that threatens future agricultural productivity and needs to be better understood. If herbicides are to remain sustainable then it is a must that we adopt diversity in crop rotations and herbicide use as well as increase the use of non-chemical measures to control weeds. Nevertheless, despite the difficulties posed by resistant weeds and increased regulatory hurdles, new screening tools promise to provide an upsurge of promising herbicide leads. Our industry urgently needs to supply agriculture with new, effective resistance breaking herbicides along with strategies to sustain their utilities.
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Introduction
Only a few companies are significantly pursuing herbicide discovery in the 21st century. Most of these have combined
seed and traits businesses since fees for traits constitute a considerable part of the income of agrochemical companies
today. In concert with the review of the historical perspectives of herbicide research (Kraehmer, et al., 2014) we
provide here a short description of the current major research activities within the remaining 21st century agrochemical
companies. After an overview of the chemicals that have entered the market in the 21st century, we provide a brief
summary of the current nature of the problem of weed resistance to herbicides. We then go on to summarise breeding-
assisted and transgenic approaches towards the improvement of crop selectivity through the delivery of so called HT
(herbicide tolerant) or HR (herbicide resistant) crops and conclude with a discussion of the new herbicide discovery
screening tools that have been employed since the year 2000 and prospects for the future.
Major chemical trends after 2000
Abbreviations for Modes of Action and Inhibitors
ACCase: acetyl-CoA carboxylase
ALS: acetolactate synthase
CBI: cellulose biosynthesis inhibitors
HPPD: 4-hyddroxphenylpyruvate dioxygenase
PPO: protoporphyrinogen IX oxidase
VLCFA: very long chain fatty acid biosynthesis
Several new compounds have entered the herbicide market in recent years. Although not representing new modes of
action, they have increased the number of tools available for farmers to control weeds. Even in known and older
herbicidal classes, new, interesting and marketable molecules have been discovered. For example, and perhaps
surprising given the relative age of the class of herbicides, new (after 2000) ALS inhibitors have provided solutions for
farmers that can be regarded as real innovations.. One of them is mesosulfuron-methyl (Figure 1), a sulfonylurea
herbicide which, when combined with iodosulfuron-methyl sodium, has broad-spectrum post-emergence grass weed
control at dose rates of 4.5-15 g a.i. ha-1 (Safferling, 2005).
Another very successful new ALS herbicide is thiencarbazone-methyl (TCM; Figure 2), a compound of the
sulfonylaminocarbonyl-triazolinone subgroup. TCM is a broad-spectrum herbicide with a maximum seasonal use rate
of 45 g a.i. ha-1 that is able to control a wide range of grasses and broadleaf weeds. Due to its lack of inherent
selectivity, utility in a crop is only possible when combined with safeners such as mefenpyr-diethyl for cereals (Veness
et al., 2008) or the new safener cyprosulfamide for corn (Santel, 2012). Different safeners thus make TCM a product
for different crops. It can be used flexibly for pre- and post-emergence weed control and is a good example of a
herbicide that can be used in multiple situations given the right mixture partners. Although TCM controls a wide
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spectrum of weeds, it has gaps that require mixture partners. For example, IFT, (Figure 3), a 4-
hydroxyphenylpyruvate dioxygenase (4-HPPD)-inhibitor which is used together with the safener cyprosulfamide,
provides a good mixture partner for TCM in the pre-emergence control of weeds in corn.A suitable mixture partner for
post-emergence applications is another 4-HPPD-inhibitor, tembotrione (Figure 3), that is marketed together with the
safener isoxadifen-ethyl. One key selling point of this mixture is that it complements the efficacy of glyphosate and
glufosinate in HT-corn and provides resistance management options especially against glyphosate resistant weeds
(Müller et al., 2007).
A third ALS inhibitor that entered the market after the year 2000 is pyroxsulam (Figure 4; Wells, 2008). The
compound belongs to the ALS subgroup triazolopyrimidine sulfonamides and controls a broad spectrum of annual
grass and broadleaf weeds with an application rate of 9-15 g a.i. ha-1. Crop selectivity is achieved in wheat, rye and
triticale varieties, in combination with the safener cloquintocet-mexyl. To complete the weed spectrum pyroxsulam is
mixed with other products, e.g., with florasulam (Figure 4). It is also sold in a mixture with pendimethalin in Europe.
Since the first registration of pyroxsulam in Chile in 2007, the compound has taken significant market share and it has
become one of the most important herbicides for cereals in Europe. It is surprising that without exception, the latest
innovative ALS solutions having a significant market impact all depend on safeners for crop selectivity.
The 4-HPPD-inhibitor herbicides have included some remarkably successful introductions over recent years especially
in corn, but also in other crops (Ahrens et al., 2013). The first 4-HPPD products pyrazolynate, pyrazoxyfen and
benzofenap (Figure 5), were introduced to the market in the 1980s, and were used in rice production in Japan with very
high application rates of up to 4 kg a.i. ha-1 (van Almsick, 2012). The first HPPD-inhibitor for corn was sulcotrione
(Figure 6), a triketone with a somewhat lower but still relatively high application rate of 300 – 450 g a.i. ha-1 for post-
emergence control of mainly broadleaf weeds. The real market success began, however, with introduction of the
second generation of the triketone HPPD-inhibitors. Mesotrione (Figure 6) represented a significant innovation not
only because it could be applied at much lower rates than the previous generation but because it could be applied
either pre- or post-emergence. Rates of only 70-150 g a.i. ha-1 in post-emergence treatments and somewhat higher
rates of 100-225 g a.i. ha-1 in pre-emergence treatments are sufficient to achieve good control of targeted weeds
(Edmunds et al., 2012). To complete the spectrum it is always mixed with other compounds, for e.g., S-metolachlor
and atrazine or alternatively with terbuthylazine in countries where atrazine is no longer registered. Since its
introduction into the USA in 2001, mesotrione has been a major success. Sales of mesotrione-based products have
been steadily increasing, such that in 2007 it was already among the five best-selling herbicides worldwide (Cheung et
al., 2008).
Isoxaflutole (Figure 3) was also developed in the late 1990s for pre-emergence use in corn (Luscombe et al., 1995).
Even though the herbicide gives excellent control of selected broadleaf and grass weeds, the necessary application
rates to achieve such a broad spectrum were near 100 g a.i. ha-1. Unfortunately such rates led to problems in crop
selectivity from time to time. With lower application rates of 75 g a.i. ha-1 the crop injury problems could be solved,
but at that rate significant weed control was lost in certain grass weeds and there was a risk of ending up with only a
broadleaf herbicide. Once again the addition of a safener made the difference, allowing the use of the higher rate. An
additional triketone HPPD-inhibitor for post-emergence control in corn, tembotrione, has recently followed sulcotrione
and mesotrione into the market (Figure 3). It offers a broader weed spectrum than the older compounds and also has
outstanding selectivity in combination with the safener isoxadifen-ethyl (van Almsick et al., 2009).. With application
rates of 75–100 g a.i. ha-1, tembotrione is able to control common grass weeds, such as foxtails (Setaria spp.) and
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woolly cupgrass (Eriochloa villosa), but also a large number of broadleaved species. This includes a few glyphosate-,
ALS-, or dicamba-resistant weeds for example. Tembotrione is not persistent in soil and therefore does not limit crop
rotation opportunities for other crops in the following seasons. Another new representative of the 4-HPPD inhibitors
is pyrasulfotole (Figure 7), a pyrazolone compound related to the above mentioned rice HPPD-inhibitors in Figure 5
(Schmitt et al., 2008). With a weed control spectrum limited to broadleaves, the compound (in mixture with
bromoxynil or MCPA) is the first, and still only, HPPD-inhibitor herbicide in the cereal market. A new mode of action
for a crop often offers the chance to control weeds that have developed herbicide resistance. This is the case of for
ALS resistant Kochia scoparia for example. Once again this compound (pyrasulfotole) needed a safener, even though
its herbicidal activity on grass weeds is very limited, and thus theoretically possesses sufficient tolerance to monocot
crops. In combination with mefenpyr-diethyl a safe post-emergence use is possible in all varieties of wheat, barley and
triticale. A further interesting aspect is the synergism of HPPD inhibitors with a photosystem II inhibitor such as
bromoxynil that helps to limit the application rate of pyrasulfotole to 25 – 50 g a.i. ha-1 and serves to broaden the
broadleaf control spectrum. Mixture partners for additional grass weed control such as fenoxaprop-P-ethyl are
required. In this case, the safener mefenpyr-diethyl works for both compounds, fenoxaprop-P-ethyl and pyrasulfotole,
even though the mode of action of both is completely different (ACCase-inhibitor and HPPD-inhibitor).
There are additional compounds which complete the newest generation of HPPD-inhibitors (Figure 8) such as
topramezone for corn or tefuryltrione for rice. Other molecules in this class such as bicyclopyrone for corn and
fenquinotrione for rice are currently in development.
Completely nonselective herbicides are rarely found and developed. One relatively new compound that entered the
nonselective market in 2010 is indaziflam (Ahrens, 2011; Figure 9). The herbicide belongs to the so called alkylazine
class and is a cellulose biosynthesis inhibitor (CBI), representing a new mode of action for this market. From the
chemical point of view the compound represents a high degree of innovation in manufacturing because of the need to
synthesize this complicated chiral compound in relatively large quantities. Indaziflam controls weeds in established
permanent crops such as tree plantations, perennial crops such as sugar cane and in turf grasses. With application rates
of 73-95 g a.i. ha-1, indaziflam provides control of weeds up to 90 days or longer after treatment. When weeds are
present at application the addition of a foliar herbicide such as glyphosate or glufosinate-ammonium is useful due to its
limited post-emergent activity. To expand the spectrum of weed control indaziflam can be mixed with a range of other
herbicides such as metribuzin and isoxaflutole.
With the success of HT-crops and the ease of post-emergence applications combined with relatively low herbicide
costs, and combined with the perceived advantages of applying a herbicide only when weed growth was observed, the
end of residual herbicides was prophesied to have arrived a while ago. The situation has recently changed with the
appearance of glyphosate-resistant weeds such as Amaranthus tuberculatus and A.palmeri. The demonstrated
advantages of using pre-emergent herbicides to reduce the population of these highly competitive weeds that germinate
over an extremely long period (Hager et al., 2002) prompted companies to develop new residual products such as
saflufenacil (Figure 10), a PPO-inhibitor (Anon, 2008). This compound can be used alone or, more important, mixed
with glyphosate and applied pre-plant for burndown applications. Saflufenacil is therefore a useful addition to a very
important segment of glyphosate-tolerant crops where glyphosate use predominates (Knezevic et al., 2009). The
compound controls primarily dicot weeds, but it controls more than 80 of them including key driver weeds resistant to
glyphosate and ALS herbicides. It can be used as a pre-emergence treatment in corn and sorghum to control major
dicot or broadleaf weeds without triazine herbicides. It can also be used as a pre-plant burn down product for other
crops.
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Another new trend in weed control is the renaissance of auxinic herbicides (Figure 11), the class that provided the first
modern herbicides (Peterson, 1967). Compounds such as aminopyralid (Masters et al., 2012, aminocyclopyrachlor
(Claus et al., 2012) and halauxifen methyl are new representatives of this long- established mode of action (Schmitzer
et al., 2013). The latter of this group is supposed to enter the market in 2014 (http://newsroom.dowagro.com/press-
release/dow-agrosciences-announces-arylex-active-global-commercial-brand-name-new-herbicide). Aminopyralid
controls primarily broadleaf weeds including noxious, poisonous and invasive plants in rangeland, pasture and
industrial vegetation management sites. It was discovered and registered in the US for non-crop and turfgrass uses for
the control of annual and perennial broadleaves and brush weeds. Halauxifen methyl is also potentially useful as a
broadleaf herbicide in selected row crops and a potential mixture partner for cereal portfolios.
The inhibition of acetyl-CoA carboxylase (ACCase) is, like ALS, one of the most commercially important modes of
action for weed management, even though ACCase inhibitors are active only on grass weeds. The
aryloxyphenoxypropionates (fops) and cyclohexanediones (dims) have been present in the marketplace for more than
30 years. The only commercially available phenylpyrazoline ACCase-inhibitor with selectivity in cereals is pinoxaden
(Figure 12; Hofer et al., 2006). The herbicide is a post-emergence graminicide for a wide range of key annual grass
species in cereals at rates of 30-60 g a.i. ha-1. It is mixed with the safener cloquintocet-mexyl as previously mentioned.
Pinoxaden shows also some activity against several ACCase-inhibitor resistant biotypes but is not active against all of
them.
A new chemical entry within a well-known mode of action is pyroxasulfone (Figure 16), which belongs to a new class
of isoxazoline herbicides and is an inhibitor of the synthesis of very long-chain fatty acids (Nakatani et al., 2012). This
new herbicide demonstrates excellent efficacy against a broad range of grass and broadleaf weeds with both pre- and
post-emergence activities. It is selective for use on corn, soybean, cereals and cotton at application rates between 50
and 250 g a.i. ha-1. More importantly, the herbicide provides effective control of trifluralin-, ALS- and ACCase-
resistant Lolium rigidum in Australia and of glyphosate-resistant Amaranthus rudis in the US. In addition, it has a
favorable soil residual profile which allows its application to be extended from the very early pre-plant stage through
post-emergence stages without consequences to following crops. The compound was discovered by Kumiai Chemical
Industry Co, Ltd and is being developed by several companies for different crops. A second compound of the same
class is fenoxasulfone (Figure 13) which is currently undergoing development as a selective rice herbicide in Japan.
Table 1 summarizes the above mentioned new herbicides of the 21st century.
Herbicide resistance
Herbicide resistance has been defined in numerous ways (HRAC, 2014; WSSA, 1998; Heap and LeBaron, 2001), but
ultimately the definitions agree that a resistant weed is one that survives and reproduces following an herbicide
treatment that would normally kill it. The selection of survivors with existing traits that are present in a population at a
relatively low frequency is generally considered to be the antecedent to resistance and is set in motion through the
intensity of selection pressure (Holt & LeBaron, 1990; Neve et al., 2009; Powles & Yu, 2010; Délye et al., 2013).
Survival of an herbicide treatment results in selection of individual plants with the enabling resistance trait or traits,
giving them an opportunity to pass these on to future generations. Several factors including the biology and genetics
of the weed species, herbicide chemistry and its mode of action (MoA), as well as key agro-ecosystem characteristics
and herbicide application and handling influence the development of herbicide resistance, which follows evolutionary
processes (Darmency, 1994; Jasienuk et al., 1996; Christoffers, 1999; Powles and Yu, 2010).
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The possibility of herbicide resistance was first predicted over 50 years ago (Harper, 1956), just over a decade after the
introduction of the first modern commercial herbicide 2,4-D in 1945 (Peterson, 1967). The first occurrences of
resistance were reported just one year after Harper’s prophetic publication in two disparate cases (Heap, 2014). We
have been living with resistance to an increasing extent ever since. After a relatively quiet period in the 1950s and
1960s, the first big wave of resistance hit the PSII inhibitors which include the triazines (HRAC Group C1), in the
1970s, which was followed a decade later by the next wave of resistance to ALS inhibitors and ACCase inhibitors
beginning in the mid-1980s (Fig. 14). It is often enlightening to revisit discussions of the past, where fears of
resistance predominantly to products with longer soil residual activity were characterized as the major issue (Anon.,
1990). This has now been eclipsed by fears of resistance to products with little to no soil residual, to products that are
primarily applied to foliage. A few years after the introduction of crops resistant to glyphosate to the North American
market in 1996, the first case of resistance development by a weed Conyza canadensis in a row crop (soybean) was
reported (VanGessel, 2001). Glyphosate resistance in weeds was, however, already detected in a population of Lolium
rigidum in Australia as early as 1995 (Pratley et al., 1996). Since then the number of weed species resistant to
glyphosate has been growing steadily (Fig. 14) and this situation has been extensively reviewed (Powles, 2008; Duke
& Powles, 2009; Nandula, 2010; Vencill et al., 2012). Much has been said therein about what is driving this
phenomenon. Despite awareness of the problem and recognition of the danger of continuing the use of glyphosate as
the sole weed control measure, many farmers have been reluctant to change (Prince et al., 2012), even if studies show
long-term benefits to proactive resistance management (Norsworthy et al., 2012). One important contributing factor in
the overall resistance predicament is that over 75% of the global herbicide market is served by herbicides from only 6
MoAs as shown in Figure 19. The situation is similar for resistance to fungicides and insecticides, where
approximately 75% of the global market is served by 6 and 4 MoAs, respectively (Casida, 2009).
The rapid adoption of glyphosate as the single weed control measure in major American row crops, particularly
soybean and cotton had a profound effect on not only farmers, but also on the agrochemical industry. It led to a loss of
overall herbicide market value, reduction in the use of other herbicides and thus directly and indirectly contributed to
significant reductions in investment into herbicide discovery (Duke, 2005; Duke, 2012). These factors and the loss of
intellectual capacity (chemists and biologists) that followed the protracted consolidation of the industry (Rüegg et al.,
2007, Duke, 2012) are partially responsible for the lack of introductions of herbicides with new modes of action over
the last two decades. The industry is still recovering from this downturn.
Resistance confirmation
The first indication of resistance to an herbicide in a field is often a report of non-performance. Many cases of
reported resistance are actually weed control failures due to other causes, attributed usually to either agronomic or
climatic factors (Bayer CropScience, unpublished results, 2014). Thus proper testing methods are extremely important
to correctly assess whether the lack of expected efficacy was due to an agronomic issue, or truly due to resistance.
There is a well-accepted approach on how to respond to a field complaint where resistance is suspected. The first step
is to record detailed field observations including the herbicide treatment history, the next step is to properly sample
seeds, and then to test them in the greenhouse using (preferably) whole pot assay techniques, and the last, but
extremely important step, is interpreting the results in the proper context (HRAC, 1999; Beckie et al., 2000; Burgos et
al., 2013). It is better to test using more than just one discriminating rate and to generate dose-response curves using
several rates in order to determine the resistance factor or index correctly (HRAC, 1999). This is particularly
important with populations that have non-target site mechanisms of resistance, especially enhanced metabolism,
because these types of resistance impart variable levels of tolerance to herbicides (Beffa et al., 2012). Fig. 15 shows
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an illustration of the variability of enhanced metabolism within populations that exhibit various degrees of enhanced
metabolism. The radiochromatograms of four individual Alopecurus myosuroides plants from five populations, two
sensitive and three resistant to mesosulfuron methyl, demonstrated relatively low levels of metabolite formation in the
sensitive plants. In a few of the sensitive plants some metabolism had occurred as shown by the presence of
metabolites. The more rapid degradation of mesosulfuron methyl in these individual plants results in a higher degree
of resistance, which is represented by the presence of greener plants among the dying, yellow plants in the pot.
However, in most of the resistant plants a large number of metabolite peaks are observed with a corresponding
decrease in the mesosulfuron methyl peak. In some of the plants the relative size of the intact mesosulfuron methyl
peak is very low compared with some of the metabolite peaks, indicating that it has been extensively metabolized and
is no longer present at a concentration high enough to injure the weed. In one plant from one of the resistant
populations, hardly any metabolism has occurred (top row middle radiochromatogram), indicating that this plant is
most likely sensitive. The accompanying photograph illustrates that plants exhibiting enhance metabolism as a
resistance mechanism can show a high degree of variability within a population, partly due to the complex polygenic
control and accumulation of resistance alleles over several selection cycles (Busi et al., 2012; Délye, 2012).
Resistance Mechanisms
Weeds have evolved numerous mechanisms of resistance that can be classified broadly into two main types, target site
and non-target site (Powles & Yu, 2010; Beckie & Tardif, 2012). Mutations to the target site that confer resistance
have been well studied whereas non-target resistance mechanisms remain less clear (Powles & Yu, 2010). The first
group of resistance mechanisms, collectively known as Target Site Resistance (TSR), includes all modifications of
proteins targeted by herbicides including gene coding sequence mutations, gene over-expression, and gene duplication
(Powles & Yu, 2010; Délye et al., 2013). TSR generally confers a relatively narrow and generally high level of
resistance to weeds within a single MoA, but digressions from this do occur (Powles & Yu; 2010). Alteration of the
target site through mutations that modify herbicide binding and thus herbicidal efficacy can usually be effected by a
single nucleotide substitution, hence making it relatively easy to select for this type of resistance (Yu & Powles, 2014).
There can be differences in resistance expression to a particular target site mutation between subgroups (chemical
classes) within a single MoA, as for example between the aryloxyphenoxyproprionate, cyclohexadione and
phenylpyrazoline classes within the ACCase inhibitors (Yu et al., 2007; Délye et al., 2008). Other types of TSR, for
e.g., enhanced enzyme expression or increased gene copy number can increase the number of active enzymes and thus
sufficiently dilute the effective relative concentration of an herbicide, conferring resistance (Gaines et al., 2010; Délye,
2012). The second group of resistance mechanisms, known collectively as Non Target Site Resistance (NTSR), where
processes not directly involving the targeted proteins such as the modification of the herbicide penetration into the
plant, decreased rate of herbicide translocation, increased rate of herbicide sequestration, or metabolism confer
resistance (Powles & Yu, 2010; Délye, 2012). NTSR, especially enhanced metabolic resistance (EMR), can confer
resistance to a much broader range of herbicides (Powles & Yu, 2010; Délye, 2012). They are surmised to develop
through an accumulation of different mechanisms and are likely polygenetic (Délye, 2012), thus theoretically more
difficult to evolve. The use of lower than full herbicide rates has been implicated in the selection of NTSR through
cycles of selection of individuals with slightly enhanced metabolism and can evolve quite rapidly (Neve & Powles,
2005; Busi et al., 2012). Especially threatening for the future are herbicide-degrading cytochrome P450 (CytP450),
glutathione-S-transferases (GST) and other enzymes potentially able to detoxify current, relatively new, and future
herbicides, even herbicides from new structural classes yet to be discovered (Powles & Yu, 2010). Despite extensive
studies and reviews of herbicide resistance, genetic issues associated with resistance evolution have not yet been
extensively investigated (Powles and Shaner, 2001, Gressel, 2002, Busi et al., 2013). Modern molecular biology
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methods, and in particular new generation sequencing, are now being implemented. Initial results have identified GST
and CytP450 genes associated with EMR (Gaines at al 2014, in press). This approach contributes not only to helping
increase our basic knowledge of this kind of resistance but also has the potential to allow development of better
diagnostic tools. As resistance becomes more complex, accurate and sensitive resistance diagnostics tools can
contribute to making the best possible weed management decisions. An integrated approach to relieve selection
pressure on herbicides is critical to preserve their usefulness.
Organizations
The Herbicide Resistance Action Committee (HRAC) is one of the organizations concerned with herbicide resistance.
It is comprised of representatives of the agrichemical industry (Table 2) whose aim is to manage resistance by
fostering a responsible attitude to herbicide use, support and promote research, understanding causes of herbicide
resistance, communication of effective resistance management strategies and collaboration with public and private
researchers (HRAC, 2014). It is supported financially by member companies and CropLife International and though
without a set structure, its members meet regularly at global and regional levels to facilitate communication between
industry members. It supports the International Survey of Herbicide-Resistant Weeds (Heap, 2014), a survey of
confirmed resistance cases and is a good resource for the current state of resistance. One of the most recognized
projects is the classification of herbicide modes of action and embodied in the “World of Herbicides” poster available
online (http://www.hracglobal.com/Portals/5/moaposter.pdf). It is revised periodically to reflect new discoveries.
HRAC supports and participates in local, regional and global research into resistance to understand its causes and
effects as well as outreach programs to bring the best and latest knowledge to management programs. Local HRAC
organizations tailor their activities to specific issues within each area.
Other organizations such as the Weed Science Society of America, the European Weed Research Society, Asian-
Pacific Weed Science Society, and la Asociación Latinoamericana de Malezas (Latin American Weed Association) are
mentioned here as examples of regional institutions sponsoring research, organizing regular conferences, meetings and
workshops on weed resistance.
Management strategies
Recommendations for best management strategies begin with understanding the biology of the targeted weeds,
understanding the situation in the particular field, using a diversified approach including pre-emergent and post-
emergent herbicides with multiple MoAs at labelled rates in sequences and mixtures, and inclusion of non-chemical
practices including cultivation “where appropriate” (Norsworthy et al., 2012; Walsh & Powles, 2014). The inclusion
of non-chemical control methods and diversified cropping systems greatly aids consistency in weed control and slows
the evolution of resistance (Beckie, 2006; Walsh & Powles, 2014). More research needs to be done in combining
chemical and non-chemical methods in order to protect the continued utility of all herbicides. In response to the
worsening resistance situation, we must reexamine our thinking about herbicides as the sole weed control technology
to be implemented simply out of convenience. We are facing the loss of many more chemical tools through resistance
if we continue to rely exclusively on them. This loss would make weed management in many crops much more
difficult, and perhaps, impossible. We must become better at implementing integrated approaches.
Future of resistance
Acknowledgment of the current status of resistance as a threat to the production of some crops and its continued
development in intensity and complexity has led to calls for new herbicide options or a new “paradigm” in weed
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control (Tranel et al., 2011). We need to understand it better. In previous years much of the work by academia and
industry focused on the goal of preventing herbicide resistance. Given the economic and other factors driving weed
control decisions on the farm, the situation is changing to resignation that resistance is inevitable, and the best result
that one can achieve is to delay the onset of resistance (Neve et al., 2011). The solution to resistance has been stated
simply – getting farmers to add diversity in their weed control programs to reduce selection pressure from any one
means of control while at the same time keeping populations sufficiently controlled (Beckie, 2006). The key is
making this argument compelling to farmers and offering effective, integrated management tools at an affordable cost.
Until industry is successful at delivering new weed control products, we must continue to protect the remaining
chemical tools and increase the integration of non-chemical tools. Once a new herbicide is discovered and introduced
into the market, all efforts should be made to protect it from the beginning of its market introduction.
Herbicide tolerant crops
Safener technologies have allowed the introduction of novel weed control solutions in a number of crops such as
cereals, rice and corn. Safeners for dicot crops such as soybeans, oilseed rape and sugarbeet, however, could not be
found despite immense screening efforts by many companies. In the past broad spectrum, one-shot weed control was
only possible with mixtures. The rapid development of breeding and molecular engineering tools at the end of the last
century led some agrochemical companies to a completely new approach: the development of herbicide tolerant crops
(HTs). The first HT crop worldwide was a glyphosate tolerant soybean from Monsanto, which was deregulated and
approved from use by growers in 1994 in the US and commercialized in 1995 (see list of other HT crops in Table 3).
The first commercial example of herbicide tolerance in crop plants in Europe, bromoxynil tolerance based upon
expression of a bacterial nitrilase gene was deregulated in 1994 (one month after the US approval for Monsantos’s
glyphosate tolerant soybeans) and entered the market in 1995 (MacKenzie, 1994). It was developed by the French
company SEITA. In 1995 several other HT crops received commercial approval in the US (e.g., Calgene: Bromoxynil
tolerance in cotton, Monsanto: Glyphosate tolerance in cotton) and Canada (e.g., AgrEvo/PGS: Glufosinate tolerance
in canola, Monsanto: Glyphosate tolerance in canola). At that time DuPont also was working on a transgenic ALS
herbicide tolerance system (James and Krattiger, 1996). From the HT traits mentioned previously, only glyphosate
and glufosinate tolerance have gained a significant market share, with glyphosate tolerance being far ahead. The
adoption of herbicide tolerance traits took place at an unprecedented speed. In 2012 herbicide tolerant soybeans and
cotton had gained a market share of 81% worldwide. In 2013 93% of soybean acreage, 85% of corn acreage and 82%
of cotton acreage in the US has been planted with HT crops (USDA, 2013). Monsanto, together along with the seed
company KWS, introduced the glyphosate tolerant sugarbeet line H7-1 in the US in 2007. Two years later, in 2009,
approximately 96% of the US sugarbeet area was planted with this genetically modified sugarbeet line (Nehls et al,
2010). The ease of use and its efficacy against a broad range of weeds made glyphosate the by far most widely used
herbicide (Powles, 2008). In the US, the lack of rotation to other HT crops and limited use of herbicides other than
glyphosate can clearly be identified as the major factors contributing to the development of glyphosate resistance.
Canadian farmers, on the other hand, have tended to rotate different HT-systems such as glyphosate-, glufosinate- and
to a much lesser degree imidazolinine-tolerant canola with, as yet, only seven cases of weeds resistant to gyphosate
documented in Canada (as of 20 June 2014) (Heap I, 2014). It is becoming clearer meanwhile, that weed management
should not rely on a single herbicide, but that it is imperative to rotate and to use mixtures of herbicides with different
modes of action. All major agrichemical companies still participating in herbicide research have reacted to this need.
In their continuous efforts to control weeds, and especially glyphosate resistant weeds, one common response from
companies has been in the area of HT crops. Many companies have now have started to transfer multiple genes
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conferring tolerance to several classes of herbicides with different modes of action into crops in order to provide
farmers with more options within a season. Corn plants tolerant to both glyphosate and glufosinate have been
developed recently. Glyphosate and glufosinate tolerant cotton plants have already been commercialized. Another
platform for corn and soybeans combines glyphosate tolerance with tolerance to 2,4-D. This particular technology is
awaiting its approval for commercialization in the US and is anticipated to enter the market in 2015. The same is true
for a platform that combines glyphosate tolerance with tolerance to dicamba, another herbicide from the auxin class is
also anticipated to enter the market in 2015. A further approach is the combination of tolerance to glyphosate with
tolerance to the sulfonylurea class of herbicides (ALS inhibitors). Finally, varieties tolerating HPPD-inhibitors plus
glyphosate and glufosinate will enter the market in a few years from now.
Mutation breeding of herbicide tolerant crops
Since the discovery of naturally occurring HT mutant plants and those not involving gene transfers, herbicide-tolerant
crops have also been conventionally bred. For instance, various herbicide-resistant canola culture systems are
currently available. Imidazolinone-tolerant Clearfield® canola was achieved through microspore mutagenesis and
selection with imazethapyr and conventional breeding. HT crops created by induced mutation and breeding are
classified as non - genetically modified crops (non-GM crops). Unlike genetically modified HT crops no heterologous
gene transfer is involved. The endogenous target gene is modified/mutated at the natural location in the plant’s
genome, thus position effects can be excluded.
Crop mutants can be created by different means (for review see Meksem and Kahl 2010). In brief the following
methods are used for HT mutant selection:
- Selection of spontaneous mutants with the herbicide
- Chemical mutagenesis and selection with the herbicide
- Chemical mutagenesis and target sequencing (Tilling*)
- Physically induced mutation with Ion beams
- Molecular breeding technologies
(*Targeting induced local lesions in genomes)
In vitro HT mutant selection: As a starting point for the selection of HT crop mutants, different plant material can be
used in plant cell and tissue culture. Depending on the crop and its properties in tissue culture, the starting materials
can be leaves, calluses, suspension cultures, protoplasts, microspore derived embryos, and immature embryo derived
cultures. However, the prerequisite for successful mutant selection experiments is that the plant material must be
rapidly growing with rapidly dividing cells that can be regenerated to fertile plants. The tissue culture approach is
advisable when spontaneous mutations are required in the target gene for herbicide tolerance.
In vivo HT mutant selection: As a starting point for the selection of HT crop mutants, plant materials can, for example,
be regenerable plant cells in tissue culture. Depending on the crop and its properties in tissue culture, the starting
materials can be leaves, calluses, suspension cultures, protoplasts, microspore derived embryos, and immature embryo
derived cultures. However, the prerequisite for successful mutant selection experiments is that the plant material must
be rapidly growing with rapidly dividing cells that can be regenerated to fertile plants. The tissue culture approach may
be preferable when spontaneous mutations are required in the target gene for herbicide tolerance. Nature can itself be a
source of non-GM HT crops with the selection of naturally occurring mutant plants. Another very successful method
to isolate HT mutants is the chemical mutagenesis of seeds e. g. with EMS, subsequently growing the seeds into the
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M1 and the M2 generation followed by selection of HT mutants through herbicide applications or identifying
mutations/mutants in the target gene through sequencing (TILLING).
ALS-Tolerant Herbicide Systems
The Clearfield® system confers tolerance to crops otherwise susceptible to imidaziloninone (ALS) herbicides. It
consists of two elements: non-GM imidazolinone tolerant crops (Tan et. al., 2005) and the respective imidazolinone
herbicides which can be used selectively in the now tolerant crop. Since 1992 the Clearfield® technology has been
consequently introduced in several crops and launched to the market as shown in Table 3. The Clearfield® system of
BASF is currently marketed as a win-win situation for the farmer and the industry. The advantages for the farmer are
more weed control options. As a result, the advantage for the company is that the herbicide active ingredients from this
class will be utilized on a much broader scale (Pfenning, 2013).
Novel weed control in non-GM sugarbeet
In Europe and countries in other regions that do not accept GM crops there is a strong demand for effective one-pass
solutions in all dicot crops due to the lack of selective herbicide innovation (e.g., for sugarbeet). Phenmedipham-based
products have contributed to reliable weed control in sugarbeet for more than 40 years. However, no fundamentally
new herbicide active ingredients in sugarbeet have come onto the market for many years, unlike in other crops like
wheat or corn. Thus, a project to select sugarbeet mutants tolerant to ALS herbicides was started in 2001 by Bayer
CropScience. The technology is based on the breeding of sugarbeet varieties that are tolerant to herbicides in the ALS-
inhibitor-class with broad-spectrum weed control (Hain et al. 2012a,b). A mutant having a naturally occurring amino
acid substitution at position 574 in the ALS enzyme, which is involved in the biosynthesis of essential branched chain
amino acids, was selected and used in further breeding. It was very important that these varieties are not a product of
transfer to the crop genome from another organism so that they could be registered in Europe as a non-GM crop. In
spring 2012 Bayer CropScience and KWS SAAT AG signed an agreement to jointly develop and commercialize this
system for weed control in sugarbeet for the global market.
The novel herbicide tolerance trait was selected in Frankfurt approximately 10 years ago using sugarbeet cell culture
techniques. Out of about 1.5 billon cells tested one herbicide tolerant cell was selected and regenerated to produce a
sugarbeet plant labelled FM12-1, forming the basis for the development of the new weed control system. The number
of cells selected is equivalent to selecting one single sugarbeet plant out of 15,000 ha of the crop. Subsequently the
HT trait has been introduced into the elite sugarbeet germplasm of KWS by marker-assisted breeding.
Non-GM SU tolerance in soybean
At DuPont Pioneer a soybean line was developed through seed mutagenesis and rounds of selection through
application of a sulfonylurea herbicide normally not tolerated by soybean (Sebastian, et al., 1989). The mutant line
displays a high degree of ALS-based resistance to both post-emergence and pre-emergence applications of a variety of
SU herbicides (Kay et al., 2014, in press).
New discovery approaches
In parallel with the development of new herbicide tolerant crops, new screening tools have been employed for the
selection of chemicals with new herbicidal modes of action. With the discovery of new highly potent low-dose
herbicide classes, specifically the sulfonylureas in the 1980s, requirements for compound quantities for herbicide
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testing decreased significantly, from grams down to the low milligram scale. Subsequently, in the mid-1990s
combinatorial chemistry, a novel synthesis tool able to produce hundreds of thousands of new chemical entities in
relatively short time, became possible (Smith, 2003; Lindell and Scherkenbeck, 2005; Scherkenbeck and Lindell,
2005; Lindell et al., 2009). As a result, plant pot-based primary screening for lead identification was replaced with
novel screening systems able to cope with high numbers of chemicals in a cost-effective way (Ridley et al., 1998). In
response to this, all major agrochemical companies introduced high-throughput screening technologies: both in-vitro
High-Through-Put-Biochemical (HTBS)- and High-Through-Put-In-Vivo (HTVS), and consequently the number of
compounds screened reached new heights (Figure 17). However, soon after the new screening technology was
adopted, it was realized that this enormous increase in screening input did not lead to the expected higher number of
strong hits and subsequent development projects (Kraehmer, 2012). As a result, screening inputs were lowered again
in favor of smaller and more diverse and targeted compound libraries (Figure 17).
From a purely statistical point of view, today an average of 140000 chemical compounds per indication need to be
screened in order to bring one new crop protection product to the market (Phillips McDougall, 2010). This translates
into 420000 compounds needed on average for a continuous product flow in all indications: fungicides, insecticides or
herbicides, including safeners.
Successful agrochemical research requires a constant input of novel chemistry to the screening cascade because, once a
chemical compound has proven to be inactive against the tested species, there is usually no reason to retest it again.
The primary objective is to find herbicidal activity. The next objective is to characterize this activity and potential for
crop selectivity. The bar at the screening level is usually set low enough to ensure that activity is found at reasonable
use rates. Sources of chemical innovations for herbicide research arise from in-house chemistry research, other
indications, life science compound pools, commercial providers, academia, natural products and others. The huge
numbers of chemical compounds being processed require large-scale automated storage and retrieval systems for
sample management, together with powerful logistics, all serving the individual indications in an efficient way.
Screening is defined as the stepwise assessment of the biological activity of a compound leading to strong candidates
for field development testing. The basic principles of compound screening in agrochemical research have been
described in several review articles (Giles, 1989; Copping, 2002; Cobb and Reade, 2010). This process can be broken
down into two main consecutive steps: Lead Finding and Lead Optimization. Usually, although sometimes named
differently, the test procedure normally consists of a primary and secondary screening, followed by field trials (Giles,
1989). As a result of the strongly increased input numbers observed at the end of the last century, high-throughput
screening systems (HTS) were introduced as initial screening tools (Figure 18). HTS in agrochemical discovery has
been reviewed recently (Tietjen et al., 2005; Drewes et al., 2012). Another approach to discover new herbicidal
precepts, consists of the systematic analysis of plant gene functions (Lein et al., 2004). This approach is expected to
aid the development of new herbicidal target assays. The study of small-molecule metabolite profiles, generally
referred to as metabolomics (Kamp et al., 2012), and gene expression profiling (GEP) (Eckes and Busch, 2012) are
valuable tools in this context. Alternatively, new herbicidal leads may also arise from the combination of whole plant
screening with physiological investigations, recently defined as physionomics (Grossmann et al., 2012). All these
approaches are covered under the general concept of systems biology, which is a more holistic approach to biological
research (Kitano, 2002).
One big advantage of agrochemical screening over pharmaceutical screening is that agrochemicals can be directly
applied to the living target organisms in early screening stages. There is no intrinsic need to start with a model system.
Relevant properties like compound uptake, speed of action, metabolism are directly covered within whole organism
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screening. However, hit identification in HTVS is limited to metabolically stable and bioavailable compounds. Any
active ingredient with marginal stability or poor bioavailability can rarely be identified with whole-organism
screening. In consequence, both techniques, HTBS and HTVS, due to their complementarity, are required in
agrochemical discovery.
In HTVS, the 96-well micro-titer plate (MTP) format is used extensively across the agrochemical industry. Substance
requirements to provide information on the herbicidal potential against selected target plants are generally low (Tietjen
et al., 2005). There are several criteria to consider concerning the plant species being used in HTVS, e.g., the size of
the seeds, germination potential, ease of visual assessment, representation of the species in downstream screening
levels, or the relative importance of the test plant with respect to the target markets.
Despite being extensively employed, use of automated 96-well MTP assessment techniques remains a challenge when
screening using HTVS. Innovations in small-scale whole plant imaging technologies remain very limited compared to
other recent developments, e.g., high content screening (HCS) or other areas of image analysis, that have taken place
in pharmaceutical research (Haney, 2008). Plant growth assessment using image analysis ideally provides a three
dimensional view, but this makes it very challenging to fulfil all requirements for fully automated systems applied to
continually growing plants. Today the numbers of sensors for plant phenotyping are numerous: RGB, Fluorescence or
NIR are standard technologies which are used for many assays with image acquisition restricted to a two-dimensional
perspective when considering the top view for micro-titer plates. The high density of plants grown in a small area
restricts the use of available standard technologies. On the other hand, there is good progress in image analysis
software. Powerful hardware and commercial imaging software enables trained users to evaluate herbicide screening
trials (also restricted to 2D) in totally different ways. The combination of new sensors, time-lapse imaging and ultra-
high quality images provide by far much deeper insights than any standard visual assessment technologies or
techniques. Software tools like, Methamorph® by Molecular Devices or the Lemnatec image analysis platforms are
well established tools to support the screener in plant phenotyping to extract useful information out of images.
With the introduction of HTS, an enormous increase in test data followed, exceeding 100,000 data points per day on
every single technology platform. These experimental raw data need to be stored in appropriate databases and
processed for the development of structure-activity-relationships (SAR). Research at Bayer CropScience for example
applies ActivityBase® from ID Business Solutions as a data management tool and Spotfire® DecisionSite for
visualization of screening results (Tietjen et al., 2005). This, together with tailored in-house information technology
solutions, permits a rapid correlation of biological results for the high numbers of chemical structures over all
screening levels. In this context, it has to be stressed that a close and effective interaction between the individual
research departments, specifically Chemistry, Biology, and Biochemistry is crucial, given the fact that the discovery of
a development candidate is primarily based on iterative cycles of syntheses and screening, thus optimizing initial lead
compounds, rather than just filtering ‘the right compound’ from a big substance pool. Finding a product like this
(merely by filtering), in fact, is a very rare event.
Abbreviations of screening terms
2D 2-Dimensional BCS Bayer CropScience HCS High-Content Screening HTS High-Throughput Screening HTBS High-Throughput Biochemical Screening HTVS High-Throughput in-Vivo Screening MTP micro-titer plate
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NIR Near Infrared RGB Red-Green-Blue SAR Structure-Activity Relationship
Outlook
The world is likely facing its biggest challenge ever in our ability to feed our global population. According to the
FAO, agricultural production must increase by 70% until 2050 to supply 9 billion people with sufficient food (FAO,
2009). Current yield trends suggest that our efforts to raise production are insufficient. A turnaround for yield
increases in broad acre crops as the basis for world food security is urgently required. Furthermore, by 2050 more than
6 billion people (67 %) will live in urban areas, ranging from an urbanization level of 86 % in developed countries to
64 % in less developed regions (United Nations, 2012). In view of limited possibilities to expand the area of arable
land, high-yielding but sustainable agriculture is the only plausible alternative. Preservation of soil, maintenance of
soil fertility and high water use efficiency, as well as maintaining high levels of local biodiversity, are of key
importance for sustainably managing the global bio-economy.
To fully exploit the maximum yield potential in crop production, weed control with management programs based upon
effective herbicides is of utmost importance for sustainable land use. Along with preventing potential yield losses,
other measures to help improve soil fertility, including minimizing wind and water erosion as well as enabling an
increase of organic matter are necessary. Today’s modern crop production has all too often abandoned diverse crop
rotations and tillage, trading them for monoculture crops and no till/low till technologies relying on an effective
herbicide technology. However, after several decades of herbicide use, weed resistance to major chemical classes
continues to spread further. Currently more than 60 % of the global herbicide market (value) is represented by
products from only 4 modes of action, all of which actually have serious resistance issues (Figure 19). With an
additional 3 modes of action, together they cover approximately 80% of the global market in value. Due to the slower
growth of weed control markets during the past few decades, increased costs for discovering and developing new
active ingredients, as well as the impact of glyphosate crop tolerance adoption in the immense North and South
American corn and soybean markets led to significantly reduced efforts in global herbicide discovery. As a
consequence of these factors the herbicide industry has undergone a protracted consolidation process, which continues
to impact agriculture.
The analysis of published patent applications for new active ingredient indicates a striking decrease of the numbers of
applications since 1990 (Fig. 20). It is obvious that only a very small group of companies remain actively engaged in
discovery of novel herbicide candidates. A review of the known development pipeline shows the same tendency. It is
estimated that from now until 2020 only 5–10 new herbicides will enter the market. Another indication of the effects
of the market forces on herbicide discovery is the number of products introduced by decade. Whereas approximately
50 new active ingredients were introduced per decade in the eighties and nineties of the last century only circa 20
herbicides were launched within the last decade (Fig. 21).
Due to an increasing lack of effective herbicide solutions and an increase in multiple resistant populations, weed
control has become more complex in order to combat resistant weed species in major broad acre crops. The soaring
agro-economy as well as greater inputs into weed management has induced further growth of the herbicide market,
which will exceed 20 bn€ per year by 2020 (BASF News Release 10 Mar 2011, Crop Protection pipeline value jumps
to € 2.4 billion. http://www.agro.basf.com/agr/AP-
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Internet/en/function/conversions:/publish/content/news_room/news/downloads/11-03-10-press-release-basf-crop-
protection-pipeline-value-jumps-to-2.4-billion-eur.pdf). The demand for new resistance management solutions is
rewarding the renewed focus on herbicide discovery. However, the regulatory requirements to develop and register
new herbicides are ever increasing, especially in Europe. Consequently, the total cost for discovery and development
of one new herbicidal active ingredient is approaching 200 million € (Phillips Mc Dougall, 2012). These costs could
continue to increase further.
To achieve a sufficient return on investment for those rising R & D cost the industry requires increasing business
opportunities per development candidate. The development of single new herbicides exclusively for smaller or niche
crops is economically unfavorable. The threshold for entry of new players in herbicide discovery is extremely high,
thus no new herbicide research oriented companies are expected to enter the market. However various research
institutes in China are increasingly engaged in herbicide discovery, but thus far are lacking in internationally focused,
integrated weed research entities.
Due to recent extraordinary market dynamics some companies are once again increasing their engagement in herbicide
discovery. Their main strategies are:
- Mode of action & target identification of herbicidal leads followed by high throughput screening and/or
structure based design
- Design of new herbicidal structural scaffolds with validated targets
- Agrophore synthesis strategies
To fully exploit the discovery potential, a fully integrated approach employing all state of the art technologies and
scientific approaches is essential. However, based on analysis and assessment of financial analyst publications as well
as patent applications (Figure 20), a market introduction of significant new herbicide classes having new resistance-
breaking modes of actions can probably only be expected after 2025.
Therefore in the near future all stakeholders must contribute to the sustainability of current herbicides by adopting
diversity - in crop rotations, herbicide combinations and sequences as well as other non-chemical measures. The
industry has to take responsibility to redouble its herbicide discovery efforts and supply agriculture with new, effective
resistance-breaking herbicides.
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FIGURE LEGENDS
Figure 1: The ALS-inhibitors mesosulfuron-methyl and iodosulfuron-methyl-sodium
Figure 2: The ALS-inhibitor thiencarbazone-methyl
Figure 3: The 4-HPPD-inhibitors isoxaflutole and tembotrione
Figure 4: The ALS-inhibitors pyroxsulam and florasulam
Figure 5: The first HPPD-inhibitors for rice: Pyrazolynate, pyrazoxyfen and benzofenap
Figure 6: The HPPD-inhibitors sulcotrione and mesotrione
Figure 7: The HPPD-inhibitor pyrasulfotole for cereals
Figure 8: Further HPPD-inhibitors: topramezone, tefuryltrione, bicyclopyrone and fenquinotrione
Figure 9: The CBI indaziflam
Figure 10: The PPO-inhibitor saflufenacil
Figure 11: The auxins aminopyralid, aminocyclopyrachlor and halauxifen methyl
Figure 12: The ACCase-inhibitor pinoxaden
Figure 13: Pyroxasulfone and fenoxasulfone
Figure 14. Number of resistant species for herbicides with selected sites of action (HRAC codes). Note: PSII
Inibititors Combined. With permission of Dr. Ian Heap, WeedScience.org 2014.
Figure 15. Radiochromatograms of sensitive (S) and resistant (R) Alopecurus myosuroides plants incubated with 14C-
labelled mesosulfuron methyl. The symbol ▲ indicates the position of the chromatographic peak of the intact active
substance (mesosulfuron methyl) and peaks to the left are those of inactive metabolites. From Beffa et al., 2012.
Figure 16: Selection of non-GM HT-mutants
Figure 17. Evolution of compound input to herbicide screening over time, highlighting the impact of combinatorial
chemistry (dotted circle).
Figure 18. Modern herbicide screening process based on screening technologies with numbers of compounds and
active ingredien requirements.
Figure 19: Herbicide Market 2012 per mode of action (without trait fees). Shaded background indicates MoAs with
significant resistance problems.
Figure 20: Active herbicide ingredient patent applications from 1990 until 2012
Figure 21: Active herbicide ingredient introductions by decade from 1945 until 2015
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Table 1 Summary of some new compounds developed for weed control after 2000
(MoA = mode of action, post = post-emergence application, pre = pre-emergence application)
MoA, target site Examples Use Launch date Auxins Aminopyralid Post, rangeland,
industrial sites, dicots
2005
Aminocyclopyrachlor Post, non-crop, brush control
2010
Halauxifen-methyl Post, dicots in cereals
expected 2014
Cellulose biosynthesis
Indaziflam Plantations, turf 2010
AHAS- or ALS- Inhibitors
Mesosulfuron-methyl Post, cereals, grasses
2001
Thiencarbazone-methyl
Post, cereals and corn
2008
Pyroxsulam Post, cereals, grasses
2008
HPPD-inhibitors Topramezone Post, corn 2006 Tembotrione Post, corn 2007 Pyrasulfotole Post, cereals,
dicots 2008
Tefuryltrione Post, rice 2010 Bicyclopyrone Post, corn and
sugarcane unknown
Fenquinotrione Not specified unknown
Protoporphyrinogen oxidase
Saflufenacil Pre and post, various crops
2010
ACCase Pinoxaden Post, cereals, grasses
2006
Very long chain fatty acid biosynthesis
Pyroxasulfone Pre + post; various crops, monocots and dicots
2012
Fenoxasulfone Pre + post; various crops, monocots and dicots
unknown
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Table 2. HRAC Global Member Companies
BASF
Bayer Crop Science
Dow AgrowSciences
DuPont Crop Protection
FMC
Makhteshim Agan
Monsanto
Syngenta Crop Protection
Sumitomo
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Table 3. Year of Commercial Introduction of Herbicide Tolerant Crops
Year Crop Type
1992 corn Non-transgenic
1995 canola, cotton & soybeans Transgenic
2001 wheat Non-transgenic
2002 rice Non-transgenic
2003 sunflower Non-transgenic
2006 lentils Non-transgenic
2011 winter oilseed rape Non-transgenic
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SNH
NH
N
N
OO O
CO2Me
OMe
OMe
NHSO2Me S
N NH
N N
N
OO O
I
CO2Me
OMe
Na+
mesosulfuron-methyl iodosulfuron-methyl-sodium
Figure 1: The ALS-inhibitors mesosulfuron-methyl and iodosulfuron-methyl-sodium
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SNH
NN
N
OO
S
O O
CO2MeOMe
Figure 2: The ALS-inhibitor thiencarbazone-methyl
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O
O
N
SO2Me
CF3
Cl
O
O
OH
O
SO2Me
CF3
isoxaflutole tembotrione
Figure 3: The 4-HPPD-inhibitors isoxaflutole and tembotrione
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N
N N
NNH
S
NO
O
OMe
OMe
OMe
CF3 N N N
NS
NH
F
F
OO
F
OMe
pyroxsulam florasulam
Figure 4: The ALS-inhibitors pyroxsulam and florasulam
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Cl
Cl
O
N
NO
SO
O
Cl
Cl
O
N
NO
O
Cl
Cl
O
N
NO
O
pyrazolynate pyrazoxyfen benzofenap
Figure 5: The first HPPD-inhibitors for rice: Pyrazolynate, pyrazoxyfen and benzofenap
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ClO
OH
O
SO2Me
O
OH
O NO2
SO2Me
sulcotrione mesotrione
Figure 6: The HPPD-inhibitors sulcotrione and mesotrione
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O
N
NOH
SO2Me
CF3
Figure 7: The HPPD-inhibitor pyrasulfotole for cereals
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ONO
N
NOH SO2Me
Cl
O
O
O
OH
O
SO2Me
N
OO
OH
O OMe
CF3
N
N
O
Cl
O
OH
OOMe
topramezone tefuryltrione
bicyclopyrone fenquinotrione
Figure 8: Further HPPD-inhibitors: topramezone, tefuryltrione, bicyclopyrone and fenquinotrione
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N
N
N
F
NH2NH
Chiral
SR
Figure 9: The CBI indaziflam
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N
N O
NH
SN
O OO
ClFO
CF3
Figure 10: The PPO-inhibitor saflufenacil
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N
NH2
Cl
Cl CO2H
N
N
NH2
Cl
CO2H
N
NH2
Cl
FCl
CO2Me
OMe
aminopyralid aminocyclopyrachlor halauxifen methyl
Figure 11: The auxins aminopyralid, aminocyclopyrachlor and halauxifen methyl
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Figure 12: The ACCase-inhibitor pinoxaden
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pyroxasulfone fenoxasulfone
Figure 13: Pyroxasulfone and fenoxasulfone
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Figure 14. Number of resistant species for herbicides with selected sites of action (HRAC codes). Note: PSII
Inibititors Combined. With permission of Dr. Ian Heap, WeedScience.org 2014.
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43
Figure 15. Radiochromatograms of sensitive (S) and resistant (R) Alopecurus myosuroides plants incubated with 14C-
labelled mesosulfuron methyl. The symbol ▲ indicates the position of the chromatographic peak of the intact active
substance (mesosulfuron methyl) and peaks to the left are those of inactive metabolites. From Beffa et al., 2012.
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Figure 16: Selection of non-GM HT-mutants
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Figure 17. Evolution of compound input to herbicide screening over time, highlighting the impact of combinatorial
chemistry (dotted circle).
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46
Figure 18. Modern herbicide screening process based on screening technologies with numbers of compounds and
active ingredient requirements.
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Figure 19: Herbicide Market 2012 per mode of action (without trait fees). Shaded background indicates MoAs with
significant resistance problems.
EPSPS
ALS
AuxinsACCase
PSII
VLCFA
HPPD
Others
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Figure 20: Active ingredient patent applications from 1990 until 2012
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Figure 21: Active ingredient introductions by decade from 1945 until 2015
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