Insecticide mixtures-uses, benefits and considerations.

Insecticides remain an important tool for the control of many insect pests. There has long been an interest in insecticide mixtures (in-can and tank-mix) as a means to provide the needed efficacy and/or spectrum to control many insect public health, crop pests or crop pest complexes. This aspect has become more important since insecticides developed in the last 30 years tend to be narrower in spectrum with many primarily focused on either sap-feeding or chewing insect pests. Insecticide mixtures are also seen as an important approach to insect resistance management (IRM) with certain requirements for optimal implementation. Additionally, insecticide mixtures can also address certain agronomic, commercial and intellectual property needs and opportunities. This perspective will review some of the drivers and considerations for insecticide mixtures and their potential uses. © 2024 Society of Chemical Industry.

Molecular Targets of Herbicides and Fungicides─Are There Useful Overlaps for Fungicide Discovery?

New fungicide modes of action are needed for fungicide resistance management strategies. Several commercial herbicide targets found in fungi that are not utilized by commercial fungicides are discussed as possible fungicide molecular targets. These are acetyl CoA carboxylase, acetolactate synthase, 5-enolpyruvylshikimate-3-phosphate synthase, glutamine synthase, phytoene desaturase, protoporphyrinogen oxidase, long-chain fatty acid synthase, dihydropteroate synthase, hydroxyphenyl pyruvate dioxygenase, and Ser/Thr protein phosphatase. Some of the inhibitors of these herbicide targets appear to be either good fungicides or good leads for new fungicides. For example, some acetolactate synthase and dihydropteroate inhibitors are excellent fungicides. There is evidence that some herbicides have indirect benefits to certain crops due to their effects on fungal crop pathogens. Using a pesticide with both herbicide and fungicide activities based on the same molecular target could reduce the total amount of pesticide used. The limitations of such a product are discussed.

Insecticide discovery-"Chance favors the prepared mind".

New options for pest insect control, including new insecticides, are needed to ensure a plentiful food supply for an expanding global population. Any new insecticides must meet the increasingly stringent regulatory requirements for mammalian and environmental safety, and also address the need for new chemistries and modes of action to deal with resistance to available insecticides. As underscored by a paraphrase of a quote from Louis Pasteur "Chance favors the prepared mind", the agrochemical industry uses a variety of approaches that attempt to improve on "chance" for the discovery of new insecticides. Although there are a number of approaches to the discovery of new insecticidal active ingredients (AIs), historically most insecticides are based on a pre-existing molecule or product either from a competitor or from an internal company source. As such the first examples of a new insecticide representing a new type or class of AI (First-in-Class: FIC) are important as prototypes for other AIs stimulating further spectrum, efficacy, physicochemical, and environmental safety refinements. FIC insecticides also represent a measure of innovation. Understanding the origins of these FIC compounds and the approaches used in their discovery can provide insights into successful strategies for future new classes of insecticides. This perspective will focus on an analysis of the approaches that have been used for discovery of FIC insecticides highlighting those approaches that have been the most successful and providing a reference point for current and future directions.

Molecular targets of insecticides and herbicides - Are there useful overlaps?

New insecticide modes of action are needed for insecticide resistance management strategies. The number of molecular targets of commercial herbicides and insecticides are fewer than 35 for both. Few commercial insecticide targets are found in plants, but ten targets of commercial herbicides are found in insects. For several of these commonly held targets, some compounds kill both plants and insects. For example, herbicidal inhibitors of p-hydroxyphenylpyruvate dioxygenase are effective insecticides on blood-fed insects. The glutamine synthetase-inhibiting herbicide glufosinate is insecticidal by the same mechanism of action, inhibition of glutamine synthetase. These and other examples of shared activities of commercial herbicides with insecticides through the same target site are discussed. Compounds with novel herbicide targets shared by insects that are not commercialized as pesticides (such as statins) are also discussed. Compounds that are both herbicidal and insecticidal can be used for insect pests not associated with crops or with crops made resistant to the compounds.

Natural Product-Based Crop Protection Compounds─Origins and Future Prospects.

The continuing need to protect food and fiber production to address the demands of an expanding global population requires new pest management tools for crop protection. Natural products (NPs) have been and continue to be a key source of inspiration for new active ingredients (AIs) for crop protection, accounting for 17% of all crop protection AIs. However, potentially 50% of all crop protection compounds have or could have a NP origin if NP synthetic equivalents (NPSEs, synthetic compounds discovered by other approaches but for which a NP model also happens to exist) are also considered. The real and hypothetical NPs have their greatest impact as insight for new classes of crop protection compounds. Among the different product areas, NPs have their largest influence on the discovery of new insecticides, while herbicides have been the least affected by mining NPs for new AIs. While plants have historically been the largest (60% of the total) source of NPs of AIs for crop protection, in the last 30 years, bacterial NPs have become the largest source (42% of the total) of new classes (first in class) of NP-inspired crop protection AIs. Interest in NPs for crop protection continues, an aspect that is highlighted by the notable rise in the numbers of publications and patents on this topic, especially in the last 20 years. The present analysis further illustrates the continuing interest and value in NPs as sources of and inspiration for new classes of crop protection compounds.

Impact of the nicotinic acetylcholine receptor mutation R81T on the response of European Myzus persicae populations to imidacloprid and sulfoxaflor in laboratory and in the field.

Sulfoxaflor (Isoclast™ active) is a sulfoximine insecticide that is active on a broad range of sap-feeding insects, including species that exhibit reduced susceptibility to currently available insecticides. Colonies of Myzus persicae (green peach aphid) were established from aphids collected in the field from peach (Prunus persica) and nectarine (Prunus persica var. nucipersica) orchards in France, Italy and Spain. The presence of the nicotinic acetylcholine receptor (nAChR) point mutation R81T was determined for all the colonies. Eight of the 35 colonies collected were susceptible relative to R81T (i.e., R81T absent), three of the colonies were found to be homozygous for R81T while 24 colonies had R81T present in some proportion (heterozygous). Sulfoxaflor and imidacloprid were tested in the laboratory against these M. persicae field colonies, which exhibited a wide range of susceptibilities (sulfoxaflor RR = 0.6 to 61, imidacloprid RR = 0.7 to 986) (resistance ratios, RR) to both insecticides. Although sulfoxaflor was consistently more active than imidacloprid against these field collected M. persicae, there was a statistically significant correlation across all colonies between the RRs for imidacloprid and sulfoxaflor (Pearson's r = 0.939, p < 0.0001). However, when a larger group of the colonies from Spain possessing R81T were analyzed, there was no correlation observed for the RRs between imidacloprid and sulfoxaflor (r = 0.2901, p = 0.3604). Thus, consistent with prior studies, the presence of R81T by itself is not well correlated with altered susceptibility to sulfoxaflor. In field trials, sulfoxaflor (24 and 36 gai/ha) was highly effective (~avg. 88-96% control) against M. persicae, demonstrating similar levels of efficacy as flonicamid (60-70 gai/ha) and spirotetramat (100-180 gai/ha) at 13-15 days after application, in contrast to imidacloprid (110-190 gai/ha) and acetamiprid (50-75 gai/ha) with lower levels of efficacy (~avg. 62-67% control). Consequently, sulfoxaflor is an effective tool for use in insect pest management programs for M. persicae. However, it is recommended that sulfoxaflor be used in the context of an insecticide resistance management program as advocated by the Insecticide Resistance Action Committee involving rotation with insecticides possessing other modes of action (i.e., avoiding rotation with other Group 4 insecticides) to minimize the chances for resistance development and to extend its future utility.

Innovation in insecticide discovery: Approaches to the discovery of new classes of insecticides.

The continuing demand for agrochemical insecticides that can meet increasing grower, environmental, consumer and regulatory requirements creates the need for the development of new solutions for managing crop pest insects. The development of resistance to the currently available insecticidal products adds another critical driver for new insecticidal active ingredients (AIs). One avenue to meeting these challenges is the creation of new classes of insecticidal molecules to act as starting points and prototypes stimulating further spectrum, efficacy and environmental impact refinements. A new class of insecticides is foreshadowed by the first molecule exemplifying that class (first-in-class, FIC) and offers one measure of innovation within the agrochemical industry. Most insecticides owe their discovery to competitor-inspired (i.e. competitor patents/products) or next-generation (follow-on to a company's pre-existing product) strategies. In contrast, FIC insecticides primarily emerge from a bioactive hypothesis approach, with the largest segment resulting from the exploration of new areas of chemistry/heterocycles and underexploited motifs. Natural products also play an important role in the discovery of FIC insecticides. Understanding the origins of these FIC compounds and the approaches used in their discovery can provide insights into successful strategies for future FIC insecticides. This review analyses information on historic and recently introduced FIC insecticides. Its main objective has been to identify the most successful discovery strategies for identifying new agrochemical solutions to meet the challenge of minimizing crop losses resulting from insects. © 2022 Society of Chemical Industry.

Impact of natural products on discovery of, and innovation in, crop protection compounds.

Natural products (NPs) have long been an important source of, and inspiration for, developing novel compounds to control weeds, pathogens and insect pests. In this review, we use a dataset of 800 historic, current and emerging crop protection compounds to explore the influence of NPs on the introduction of new crop protection compounds (fungicides, herbicides, insecticides) as a function of time. NPs, their semisynthetic derivatives (NPDs) and compounds inspired by NPs (NP mimics, NPMs) account for 17% of all crop protection compounds. NPs, NPDs, and NPMs have been a fairly constant source of new agrochemicals over the past 70 years. NP synthetic equivalents (NPSEs) is a fourth group of NP-related crop protection compounds composed of synthetic compounds which by chance also happen to have an NP model (but are not involved in the discovery). If NPSE compounds are also included, then 50% of all crop protection compounds hypothetically could have had a NP origin. Similar trends also hold true for the impact of NPs on the discovery of new modes of action (MoA) or innovation in crop protection compounds as measured by the number of first-in-class compounds. NPs have had the largest impact on the numbers and global sales (2018 USD) of insecticides compared to fungicides and herbicides. The present analysis highlights NPs as a long-standing and continuing source of new chemistry, new MoAs and innovation in crop protection compound discovery. © 2021 Society of Chemical Industry.

Sulfoxaflor - A sulfoximine insecticide: Review and analysis of mode of action, resistance and cross-resistance.

The sulfoximines, as exemplified by sulfoxaflor (Isoclast™active), are a relatively new class of nicotinic acetylcholine receptor (nAChR) competitive modulator (Insecticide Resistance Action Committee [IRAC] Group 4C) insecticides that provide control of a wide range of sap-feeding insect pests. The sulfoximine chemistry and sulfoxaflor exhibits distinct interactions with metabolic enzymes and nAChRs compared to other IRAC Group 4 insecticides such as the neonicotinoids (Group 4A). These distinctions translate to notable differences in the frequency and degree of cross-resistance between sulfoxaflor and other insecticides. Most insect strains exhibiting resistance to a variety of insecticides, including neonicotinoids, exhibited little to no cross-resistance to sulfoxaflor. To date, only two laboratory-based studies involving four strains (Koo et al. 2014, Chen et al. 2017) have observed substantial cross-resistance (>100 fold) to sulfoxaflor in neonicotinoid resistant insects. Where higher levels of cross-resistance to sulfoxaflor are observed the magnitude of that resistance is far less than that of the selecting neonicotinoid. Importantly, there is no correlation between presence of resistance to neonicotinoids (i.e., imidacloprid, acetamiprid) and cross-resistance to sulfoxaflor. This phenomenon is consistent with and can be attributed to the unique and differentiated chemical class represented by sulfoxalfor. Recent studies have demonstrated that high levels of resistance (resistance ratio = 124-366) to sulfoxaflor can be selected for in the laboratory which thus far appear to be associated with enhanced metabolism by specific cytochrome P450s, although other resistance mechanisms have not yet been excluded. One hypothesis is that sulfoxaflor selects for and is susceptible to a subset of P450s with different substrate specificity. A range of chemoinformatic, molecular modeling, metabolism and target-site studies have been published. These studies point to distinctions in the chemistry of sulfoxaflor, and its metabolism by enzymes associated with resistance to other insecticides, as well as its interaction with insect nicotinic acetylcholine receptors, further supporting the subgrouping of sulfoxaflor (Group 4C) separate from that of other Group 4 insecticides. Herein is an expansion of an earlier review (Sparks et al. 2013), providing an update that considers prior and current studies focused on the mode of action of sulfoxaflor, along with an analysis of the presently available resistance / cross-resistance studies, and implications and recommendations regarding resistance management.

Structure Simplification of Natural Products as a Lead Generation Approach in Agrochemical Discovery.

Natural products (NPs) have a long history as sources of compounds for crop protection. Perhaps a more important role for NPs has been as models and inspiration for the discovery and development of synthetic crop protection compounds. NPs and their synthetic mimics account for 18% of all crop protection compounds, whereas another 38% of all crop protection compounds have a NP that could have served as a model. Because NPs are often complex molecules, have limited availability, or possess structural features that constrain their suitability for use in agricultural settings, a key element in NP-inspired compounds is the simplification of the NP structure to provide a synthetically accessible molecule that possesses the physicochemical properties needed for use in crop protection. Herein we review a series of examples of NP mimics that demonstrate the structural or synthetic simplification of NPs as a guide for the discovery of future NP-inspired agrochemicals focused on fungicides, herbicides, and insecticides.

East meets west: regional impact on agrochemical discovery and innovation.

The efficient production of the food needed to nourish an expanding global population continues to fuel the demand for new crop protection compounds. This task is made all the more difficult by the need to meet increasingly demanding grower, consumer and regulatory constraints. The discovery and development of new synthetic organic crop protection compounds has been largely the responsibility of the agrochemical industry in Europe, Japan and the USA, with government-funded academic research often playing a crucial role in the early stages of the invention and testing of novel activity. The way in which this process takes place has undergone a dramatic evolution over the past 75 years. Drastic consolidation and globalization among the research and development (R&D)-based companies in these regions have characterized these changes. This evolution in the agrochemical industry has, in turn, shaped the rate of introduction and geographic origin of new crop protection compounds. In spite of these changes, the rate of invention of new classes of crop protection compounds has remained relatively constant. During the past 30 years, the forefront of new compound introductions has moved towards Asia, and Japan in particular. Although there are now more agrochemical companies in Japan involved in the discovery and development of new crop protection compounds than in Europe and the USA combined, on a compound-per-company basis, US companies currently generate the highest output. However, it is expected that there will continue to be changes in the numbers and origins of new crop protection compounds, with contributions continuing from Europe, Japan and the USA, and increasingly from China. © 2021 Society of Chemical Industry.

Role of nicotinic acetylcholine receptor subunits in the mode of action of neonicotinoid, sulfoximine and spinosyn insecticides in Drosophila melanogaster.

Insecticides remain valuable tools for the control of insect pests that significantly impact human health and agriculture. A deeper understanding of insecticide targets is important in maintaining this control over pests. Our study systematically investigates the nicotinic acetylcholine receptor (nAChR) gene family, in order to identify the receptor subunits critical to the insect response to insecticides from three distinct chemical classes (neonicotinoids, spinosyns and sulfoximines). Applying the CRISPR/Cas9 gene editing technology in D. melanogaster, we were able to generate and maintain homozygous mutants for eight nAChR subunit genes. A ninth gene (Dß1) was investigated using somatic CRISPR in neural cells to overcome the low viability of the homozygous germline knockout mutant. These findings highlight the specificity of the spinosyn class insecticide, spinosad, to receptors containing the Dα6 subunit. By way of contrast, neonicotinoids are likely to target multiple receptor subtypes, beyond those receptor subunit combinations previously identified. Significant differences in the impacts of specific nAChR subunit deletions on the resistance level of flies to neonicotinoids imidacloprid and nitenpyram indicate that the receptor subtypes they target do not completely overlap. While an R81T mutation in ß1 subunits has revealed residues co-ordinating binding of sulfoximines and neonicotinoids differ, the resistance profiles of a deletion of Dß1 examined here provide new insights into the mode of action of sulfoxaflor (sulfoximine) and identify Dß1 as a key component of nAChRs targeted by both these insecticide classes. A comparison of resistance phenotypes found in this study to resistance reported in insect pests reveals a strong conservation of subunit targets across many different insect species and that mutations have been identified in most of the receptor subunits that our findings would predict to have the potential to confer resistance.

Crop protection compounds - trends and perspective.

The Industry responsible for the discovery and development of crop protection compounds has undergone dramatic changes and increasing consolidation since the initial innovations in synthetic organic fungicides, herbicides and insecticides in the late 1940s and early 1950s. Likewise, there have been striking changes in the rate of introduction of new crop protection compounds over the past 70 years. While numerous studies over the past five decades have signaled the ongoing decline in the numbers of new active ingredients (AIs), a detailed analysis of the trends in the rate of introduction of crop protection compounds shows a more complex pattern in the overall output of new AIs. The recent (post-2000) decline in the numbers of new herbicides is the primary source of the perceived decline in overall numbers. When herbicides are excluded, the output of new fungicides and insecticides has been relatively constant, especially for the past 20 years. A notable observation is that innovation, as measured by the number of compounds representing a new chemical class (First-in-Class) has been relatively constant for the past 70 years, and most recently has been driven by the appearance of new fungicides and insecticides. Thus, the discovery and development of new AIs for crop protection and public health continues, in spite of the many challenges and changes to the Industry. © 2021 Society of Chemical Industry.

Insecticide resistance management and industry: the origins and evolution of the Insecticide Resistance Action Committee (IRAC) and the mode of action classification scheme.

Insecticide resistance is a long-standing problem affecting the efficacy and utility of crop protection compounds. Insecticide resistance also impacts the ability and willingness of companies around the world to invest in new crop protection compounds and traits. The Insecticide Resistance Action Committee (IRAC) was formed in 1984 to provide a coordinated response by the crop protection industry to the problem of insecticide resistance. Since its inception, participation in IRAC has grown from a few agrochemical companies in Europe and the US to a much larger group of companies with global representation and an active presence (IRAC Country Groups) involving an even wider array of companies in more than 20 countries. The focus of IRAC has also evolved from that of defining and documenting cases of insecticide resistance to a pro-active role in addressing insecticide resistance management (IRM) providing an array of informational and educational tools (videos, posters, pamphlets) on insect pests, bioassay methods, insecticide mode of action and resistance management, all publicly available through its website (https://irac-online.org/). A key tool developed by IRAC is the Insecticide Mode of Action (MoA) Classification Scheme, which has evolved from a relatively simple acaricide classification started in 1998 to the far broader scheme that now includes biologics as well as insecticides and acaricides. A separate MoA Classification Scheme has also been recently developed for nematicides. The IRAC MoA Classification Scheme coupled with expanding use of MoA labeling on insecticide and acaricide product labels provides a straightforward means to implement IRM. An overview of the history of IRAC along with some of its notable accomplishments and future directions are reviewed. © 2021 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

The spinosyns, spinosad, spinetoram, and synthetic spinosyn mimics - discovery, exploration, and evolution of a natural product chemistry and the impact of computational tools.

Natural products (NPs) have long been a source of insecticidal crop protection products. Like many macrolide NPs, the spinosyns originated from a soil inhibiting microorganism (Saccharopolyspora spinosa). More than 20 years after initial registration, the spinosyns remain a unique class of NP-based insect control products that presently encompass two insecticidal active ingredients, spinosad, a naturally occurring mixture of spinosyns, and spinetoram, a semi-synthetic spinosyn product. The exploration and exploitation of the spinosyns has, unusually, been tied to an array of computational tools including artificial intelligence (AI)-based quantitative structure activity relationship (QSAR) and most recently computer-aided modeling and design (CAMD). The AI-based QSAR directly lead to the discovery of spinetoram, while the CAMD studies have recently resulted in the discovery and building of a series of synthetic spinosyn mimics. The most recent of these synthetic spinosyn mimics show promise as insecticides targeting lepidopteran insect pests as demonstrated by field studies wherein the efficacy has been shown to be comparable to spinosad and spinetoram. These and a range of other aspects related to the exploration of the spinosyns over the past 30 years are reviewed herein. © 2020 Society of Chemical Industry.

Insecticides, biologics and nematicides: Updates to IRAC's mode of action classification - a tool for resistance management.

Insecticide resistance has been and continues to be a significant problem for invertebrate pest control. As such, effective insecticide resistance management (IRM) is critical to maintain the efficacy of current and future insecticides. A technical group within CropLife International, the Insecticide Resistance Action Committee (IRAC) was established 35 years ago (1984) as an international association of crop protection companies that today spans the globe. IRAC's focus is on preserving the long-term utility of insect, mite, and most recently nematode control products through effective resistance management to promote sustainable agriculture and improved public health. A central task of IRAC has been the continual development and documentation of the Mode of Action (MoA) Classification scheme, which serves as an important tool for implementing IRM strategies focused on compound rotation / alternations. Updates to the IRAC MoA Classification scheme provide the latest information on the MoA of current and new insecticides and acaricides, and now includes information on biologics and nematicides. Details for these new changes and additions are reviewed herein.

Sulfoxaflor efficacy in the laboratory against imidacloprid-resistant and susceptible populations of the green peach aphid, Myzus persicae: Impact of the R81T mutation in the nicotinic acetylcholine receptor.

A key to effective insect pest management and insecticide resistance management is to provide growers with a range of new tools as potential alternatives to existing compounds or approaches. Sulfoxaflor (Isoclast™ active) is a new sulfoximine insecticide which is active on a broad range of sap-feeding insects, including species that have reduced susceptibility to currently used insecticides, such as imidacloprid from the neonicotinoid class. Sulfoxaflor (SFX) and imidacloprid (IMI) were tested in laboratory bioassays to compare the susceptibility of field populations of green peach aphid, Myzus persicae (Sulzer), exhibiting varying degrees of resistance involving an alteration (R81T) to the insect nicotinic acetylcholine receptor. The LC50 values for M. persicae exposed to SFX ranged from 0.09 to 1.31 (mg litre-1), whereas when the same populations were exposed to IMI the LC50 values ranged from 0.6 to 76.2 (mg litre-1). M. persicae were significantly more sensitive to SFX as compared to IMI for nine of the 13 populations tested. For M. persicae populations confirmed to be homozygous susceptible (ss) or heterozygous rs) for the R81T point mutation, there was no significant differences in the observed LC50 values for either SFX or IMI relative to the susceptible reference population (15LP1). However, in all M persicae populations that were homozygous (rr) for the R81T point mutation, susceptibility was significantly less to IMI as compared to the reference population with resistance ratios ranging from 22.1 to 63.5-fold. In contrast, only one homozygous resistant population (15MP9) exhibited a statistically significant change in susceptibility (RR = 10-fold) to SFX as compared to the reference population, which was far less than the 56-fold observed for imidacloprid in that same population. Thus, this study indicates there is no specific correlation between the laboratory efficacy of SFX and IMI in field collected populations in Spain displaying varying degrees of resistance to IMI. Furthermore, the presence of target site resistance in M. persicae to IMI, in the form of the R81T mutation, does not a priori translate to a reduction in sensitivity to sulfoxaflor. Consequently, SFX can be an effective tool for use in insect pest management programs for green peach aphid. These data also serve as a baseline reference for green peach aphid sensitivity to SFX prior to commercial uses in Spain.

Intellectual property in entomology: Analysis and perspective on recent trends in global patent publications.

Intellectual property (IP) is an important consideration for entomological research and provides a means to capture value from new discoveries. Herein, we describe an analysis of more than 26 000 patent publications from 2007-2017 related to the field of entomology. These patents were divided among 8000 patent assignees; however, only 5% of the assignees had ≥10 patents. Corporations accounted for the largest share of patents (59%), with individuals (20%), academic institutions (17%) and government organizations (4%) making up the remaining segments. From 2007-2017 the number of entomological patents increased by 400%, with the largest number being from China. However, unlike patents from Europe, Japan or the US, which target a range of countries, the Chinese patents almost exclusively focus on China. Among the array of subjects covered are transgenic insects and plants, repellents, recombinant insect cells, with the highest proportion of patents focused on insecticides (39%), followed by insecticide mixtures (27%) and formulations (21%). The top 30 patent assignees included companies/institutions from China (18), Europe (3), Japan (6) and the US (3). Among the top 12 entities, IP from the US assignees was distributed across insecticides, mixtures and insecticidal traits while those from China were more focused on mixtures. However, given expanding IP numbers from China it is expected that in the future there will be a greater impact on new insecticides and related technologies. © 2020 Society of Chemical Industry.