Herbicide discovery has followed various approaches since the first selective herbicides, such as the auxins 2,4-D and MCPA were invented serendipitously in the 1940s. Scientists were looking for agents to stimulate plant growth. However, it was observed that when broadleaved weeds were inadvertently treated with these molecules they developed the familiar twisting and curling symptomology, shrivelled and desiccated.
Since then, random screening, inspiration from complex natural molecules and patent busting have all been successful strategies filling R&D pipelines in the past.
In the 21st century, though, the rate at which new herbicide active ingredients have been introduced to the market has slowed considerably. Conventionally, screening had been based on whole-plant primary and then more focused secondary screens. Screening rates were typically 10,000 - 20,000 compounds/year in large crop protection discovery companies. The adoption of high throughput screening (HTS) allowed screening rates of hundreds of thousands of compounds/year in in vitro test systems. Despite great optimism, few successes resulted.
Fewer new herbicides
The chart shows the progress of development molecules progressing through of industry pipelines over the past three decades. Since the late 1990s, new herbicides are reaching the market at a much slower rate. Many of the biggest selling and most widely used active ingredients, e.g. glyphosate, have been used by farmers for decades.
The problem for global crop protection is very serious, because the new herbicides becoming available to farmers are from the same few modes of action and this has led to resistant weeds.
Glyphosate is a particularly topical example where resistant weeds are causing huge problems in major crops like cotton, maize and soybeans in North and South America. The best current approach has been one of damage limitation to allow the continued use of glyphosate. These important crops have been genetically modified to be tolerant to both glyphosate and the very old broadleaved weed herbicides 2,4-D and dicamba. These active ingredients can be mixed with glyphosate to control the weeds that glyphosate now misses.
No new modes of action
Mode of action refers to the biochemical mechanism by which a herbicide kills a weed. In most cases this is because the herbicide molecule inhibits an enzyme from making a protein. Some others interfere with photosynthesis. There about 25 commercial herbicide modes of action, but most widely used products come from just a few. The history of the commercialisation of new herbicide modes of action is shown in the chart below.
Until the late 1980s the agrochemical industry had been regularly commercialising herbicides with novel modes of action. However, since the introduction of the first inhibitors of 4-hydroxyphenyl-pyruvate-dioxygenase (HPPD) no significant new herbicide modes of action have been commercialised.
The HPPD inhibitor herbicides sulcotrione, mesotrione and isoxaflutole were introduced in the 1990s, but it is often forgotten that several HPPD inhibitors (pyrazolates) were commercialised as rice herbicides some years earlier in the Far East.
The consequences of no new herbicide modes of action being available have been dire. Herbicide resistant weeds have devastated countless fields of valuable crops worldwide, significantly reducing yields as well as increasing weed control and harvesting costs.
A first reaction has often been to use higher rates of a herbicide in order to control a resistant weed, but this leads to more resistance and more environmental impact. Using old herbicides as discussed above runs the risk of environmental problems and of resistance ultimately becoming a problem with them as well.
In some cases farmers have been forced to resort to increased tillage of the land to control weeds thereby destroying fertile topsoil causing soil erosion, encouraging surface water runoff and releasing carbon into the atmosphere.
In the most extreme cases farmers have resorted to controlling weeds using blow torches or hand weeding, neither of which are environmentally desirable nor economically viable.
Why is herbicide discovery difficult?
A number of different reasons have been suggested to be behind this dearth of new modes of action These are summarised in the table opposite.
In addition, in the past, leads were selected from whole-plant screens on the basis of their symptomology by expert herbicide biologists. The move to HTS in vitro screens effectively pre-screened the input into whole plant tests, lessening the probability of observing novel symptomology.
Serendipity has also played a role. Chance observations from Nature have sometimes provided the inspiration or starting points for very successful crop protection active ingredients (see the Triketone story below). This may prove fruitful in future utilising new technologies to identify novel modes of action with potentially attractive commercial profiles of activity, physico-chemical, toxicological and eco-toxicological properties; and to identify the essential parts of often highly complex molecules.
Herbicides from nature: the story of the triketones
A weed scientist pondering the absence of weeds underneath a garden shrub in San Francisco in 1977 led to the discovery of a new herbicide mode of action and a family of successful products.
Callistemon citrinus, the bottlebrush plant (left), secretes leptospermone (an acylsyncarpic acid), which is an allelopathic molecule that inhibits weed growth.
The performance of this natural compound on herbicide screens was modest, but enough to signal a lead. The white bleaching effect was found to be due to inhibition of 4-hydroxyphenylpyruvate dioxygenase (HPPD), a new mode of action. A programme of analogue synthesis, physiological studies and screening boosted activity, improved crop selectivity and reduced soil persistence.
The first triketone HPPD inhibitor, sulcotrione, was commercialised as a maize herbicide in 1991. It has been followed by a number of others, with improved activity and different spectrums of weed control with selectivity to different crops.
References and further reading
Duke, S O (2012). Why have no new herbicide modes of action appeared in recent years? Pest Management Science, 68, (4), 505-512
Mitchell G et al. (2001). Mesotrione: a new selective herbicide for use in maize. Pest Management Science, 57, 120-128
Peters, B and Strek, H J (2017). Herbicide discovery in light of rapidly spreading resistance and ever‐increasing regulatory hurdles. Pest Management Science, 74, (10), 2211-2215
Westwood, J H et al. (2018). Weed Management in 2050: Perspectives on the Future of Weed Science. Weed Science, 66, (3), 275-285