ReviewThe new age of insecticide discovery-the crop protection industry and the impact of natural products
Graphical abstract
Timeline for the major classes of insecticides highlighting the numbers of different active ingredients (AIs) in each class. A trendline for the size of the classes shows that, in general, the numbers of AIs in each class have gotton smaller. Also highlighted are the early insecticide classes assocated with the ‘Goldern Age” of insecticide discovery and those commercalized since 1990 representing a ‘New Age” of insecticide discovery yeilding a far greater in number of new insecticide classes than the prior 50 years.
Introduction
The discovery of new tools to control pest insects has been a critical need for centuries and continues today with the requisite of feeding an expanding global population (Godfray et al., 2010) and addressing the longstanding threats from insect borne diseases. Although there are many techniques and technologies for pest insect control including biological control, transgenic plants, host plant resistance, cultural controls, and increasingly biopesticides (Gunther and Jeppson, 1960; National Academy of Sciences, Insect-Pest Management and Control, 1969; National Academy of Sciences, 1972; Gross et al., 2014; Sparks and Lorsbach, 2017a), for many crop-pest-geography scenarios insecticides remain a critical component. Early solutions included natural products (NPs) such as nicotine and pyrethrum (Table 1), along with inorganic options such as sulfur and the arsenicals (Shepard, 1951; Casida and Quistad, 1998). A major transformation in pest insect control began during the 1940s and 1950s, with the introduction of synthetic organic insecticides such as DDT, organophosphates (OPs), cyclodienes, and N-methylcarbamates (Table 1). The late 1940s through the 1960s has been referred to as the “golden age of insecticide discovery” (Gubler, 1983; Achilladelis et al., 1987; Casida and Quistad, 1998), as highly effective, reliable and affordable pest insect control became commonplace. However, during this same time period, there was an expanded rise in insecticide resistance (Fig. 1). The rise in resistance, coupled with increasing concerns about mammalian and environmental toxicology of the available insecticides fueled the introduction of integrated pest management (IPM), and the quest for more selective insecticides that during subsequent decades resulted in numerous new additions to the existing insecticide classes (Table 1).
During the last 50 years, the crop protection industry has been successful in improving many attributes of new insecticides including improving the insecticide selectivity and lowering use rates (Sparks, 2013). Although the environmental profiles for new insecticides have improved over the past several decades, further improvement around attributes related to environmental impact continue to be an essential goal, driven in large part by increasingly stringent regulatory requirements, and public expectations for more environmentally friendly options (Lamberth et al., 2013; Sparks, 2013; Corsi and Lamberth, 2015; Maienfisch and Stevenson, 2015; Sparks and Lorsbach, 2017b; Kalaitzandonakes and Zahringer, 2018; Nishimoto, 2019). Likewise, insect resistance to the available insecticides (National Academy of Sciences, 1969; Menn and Henrick, 1985; Hodgson and Kuhr, 1990; Lamberth et al., 2013; Sparks and Nauen, 2015; Sparks and Lorsbach, 2017b; Kalaitzandonakes and Zahringer, 2018) also continues to be another key driver, with the numbers of cases of resistance continuing to rise (Fig. 1) (Whalon et al., 2008; Tabashnik et al., 2014; Sparks and Nauen, 2015; Tabashnik and Carrière, 2017). Thus, new insecticides, ideally possessing new MoAs and further improvements to environmental profiles are needed to provide new options for insecticide resistance management (IRM) programs (Sparks and Nauen, 2015; Roush, 1989; Thompson and Leonard, 1996; Elbert et al., 2007; Nauen et al., 2019; Insecticide Resistance Action Committee (IRAC), 2019) and provide growers with new options that to meet or exceed current and future environmental standards.
Section snippets
The crop protection industry enters a new age of insecticide discovery
The discovery and commercialization of new insecticides has become progressively expensive, approaching, on average, $300 million USD, due to lengthened timelines and increased costs for the development and registration of new products (Lamberth et al., 2013; Corsi and Lamberth, 2015; Sparks and Lorsbach, 2017b). These factors have driven changes in the crop protection industry, in particular, consolidation among the companies (Fig. 2). During the first few decades of synthetic pesticide
Numbers of insecticide modes of action
The insecticide market of the 1950s and 1960s was dominated by only a few classes of insecticides that included the DDT and its analogs, cyclodienes (and associated organochlorines), OPs, and the N-methyl carbamates (Table 1, Fig. 3, Fig. 4). These chemistries relied on just three MoAs: modulation of the voltage-gated sodium channel (VGSC), inhibition of acetylcholinesterase (AChE), and block of the gamma-aminobutyric acid (GABA)-gated chloride channel (Table 1). Together these groups of
Discovering new insecticides: lead generation
Historically, there has been a wide range of approaches to insecticide discovery that has included empirical/random screening of chemical libraries, NPs as potential products and inspiration, various forms of biochemical (target-site) or bio-rational design, the open literature, competitor patents, biologically active scaffolds, internal datamining/broad screening of other areas of chemistry (herbicides and fungicides), and novel chemical scaffolds (Braunholtz, 1977; Menn, 1980; Eder and von
Summary–new age of insecticide discovery
As highlighted above, in many respects the past 27 years denotes a new age of insecticide discovery, with the creation of many new classes of insecticidal chemistry (e.g., neonicotinoids, diamides, diacylhydrazines, spinosyns, sulfoximines, meta-diamides, isoxazolines, pyropenes, etc.) and the discovery of several new MoAs (Table 1). Such a viewpoint is supported by the fact that there have been twice as many new classes of insecticidal chemistries commercialized with significant sales (≥50 MM
Acknowlegements
We thank Dr. Rob Bryant (Agranova) for permission to report summarized sales data, Drs. Vidyadhar Hegde, James Hunter and Jeffrey Nelson (Corteva Agriscience) for useful comments and discussion, Dr. David Mota-Sanchez (Michigan State University) for recent data on the status of insecticide resistance, and the late Dr. John Casida (University of California Berkeley) for inspiration leading to some of the ideas expressed herein. This research was funded by Corteva Agrisciences. The ideas
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