Thomas C. Sparks

Spinosad – a case study: an example from a natural products discovery programme†

The discovery and characterization of the soil actinomycete, Saccharopolyspora spinosa, and the insecticidal metabolite spinosad is presented as a case history of a successful project emerging from a natural products crop protection discovery programme. A who, what and how approach is utilized to communicate the events around the discovery and development of the project. The companies and departments involved are listed with insight into their structure and philosophy. A detailed description of spinosad and its properties is also provided. Finally an overview is given of the various tasks required and hurdles that were overcome to bring the project to a commercial success. © 2000 Society of Chemical Industry

IRAC: Mode of action classification and insecticide resistance management

Insecticide resistance is a long standing and expanding problem for pest arthropod control. Effective insecticide resistance management (IRM) is essential if the utility of current and future insecticides is to be preserved. Established in 1984, the Insecticide Resistance Action Committee (IRAC) is an international association of crop protection companies. IRAC serves as the Specialist Technical Group within CropLife International focused on ensuring the long term efficacy of insect, mite and tick control products through effective resistance management for sustainable agriculture and improved public health. A key function of IRAC is the continued development of the Mode of Action (MoA) classification scheme, which provides up-to-date information on the modes of action of new and established insecticides and acaricides and which serves as the basis for developing appropriate IRM strategies for crop protection and vector control. The IRAC MoA classification scheme covers more than 25 different modes of action and at least 55 different chemical classes. Diversity is the spice of resistance management by chemical means and thus it provides an approach to IRM providing a straightforward means to identify potential rotation/alternation options.

Discovery and Characterization of Sulfoxaflor, a Novel Insecticide Targeting Sap-Feeding Pests

The discovery of sulfoxaflor [N-[methyloxido[1-[6-(trifluoromethyl)-3-pyridinyl]ethyl]-λ(4)-sulfanylidene] cyanamide] resulted from an investigation of the sulfoximine functional group as a novel bioactive scaffold for insecticidal activity and a subsequent extensive structure-activity relationship study. Sulfoxaflor, the first product from this new class (the sulfoximines) of insect control agents, exhibits broad-spectrum efficacy against many sap-feeding insect pests, including aphids, whiteflies, hoppers, and Lygus, with levels of activity that are comparable to those of other classes of insecticides targeting sap-feeding insects, including the neonicotinoids. However, no cross-resistance has been observed between sulfoxaflor and neonicotinoids such as imidacloprid, apparently the result of differences in susceptibility to oxidative metabolism. Available data are consistent with sulfoxaflor acting via the insect nicotinic receptor in a complex manner. These observations reflect the unique structure of the sulfoximines compared with neonicotinoids.

THE HAEMOLYMPH JUVENILE HORMONE ESTERASE OF MANDUCA SEXTA (L.)--INHIBITION AND REGULATION

A number of compounds were screened as potential juvenile hormone esterase (JHE) inhibitors, of which O-ethyl-S-phenyl phosphoramidothiolate was found to be the most potent (150 = 4 × 10 -9 M). Gel filtration of the haemolymph resolved only one peak of enzyme activity capable of rapidly hydrolyzing juvenile hormone (JH). JHE titres were monitored during the last instar in wild type and black mutant larvae of Manduca sexta (L.). In wildtype larvae the increase in JHE activity was most rapid during the first 18 h and then became a function of weight until mid-day three. Although the prewandering peak of the JHE activity occurred on day three in both strains, the JHE activity peak was greatly reduced in black mutant and allatectomized larvae. JHE activity was induced in freshly ecdysed final stadium larvae by juvenoid applications. When pharate fifth stadium larvae were either neck- or abdomen-ligated, or when freshly ecdysed larvae were starved, the levels of JHE activity remained low and could not be induced by juvenoids. Thus, JH may complement the action, or stimulate the production of an unknown factor(s) responsible for increasing JHE activity during the prewandering phase. Both strains also possessed a second smaller JHE activity peak of identical size just prior to pupation (day eight). Just prior to pupation the haemolymph JHE activity can be induced by epofenonane to higher than normal levels in black mutant and in allatectomized larvae, as well as in untreated insects, suggesting that JH directly stimulates the second JHE peak. Key Word Index: Manduca sexta (L.), juvenile hormone, juvenile hormone esterase, regulation, inhibition, phosphoramidate, allatectomy, gel filtration

Biological characterization of sulfoxaflor, a novel insecticide

BACKGROUND The commercialization of new insecticides is important for ensuring that multiple effective product choices are available. In particular, new insecticides that exhibit high potency and lack insecticidal cross-resistance are particularly useful in insecticide resistance management (IRM) programs. Sulfoxaflor possesses these characteristics and is the first compound under development from the novel sulfoxamine class of insecticides. RESULTS In the laboratory, sulfoxaflor demonstrated high levels of insecticidal potency against a broad range of sap-feeding insect species. The potency of sulfoxaflor was comparable with that of commercial products, including neonicotinoids, for the control of a wide range of aphids, whiteflies (Homoptera) and true bugs (Heteroptera). Sulfoxaflor performed equally well in the laboratory against both insecticide-susceptible and insecticide-resistant populations of sweetpotato whitefly, Bemisia tabaci Gennadius, and brown planthopper, Nilaparvata lugens (Stål), including populations resistant to the neonicotinoid insecticide imidacloprid. These laboratory efficacy trends were confirmed in field trials from multiple geographies and crops, and in populations of insects with histories of repeated exposure to insecticides. In particular, a sulfoxaflor use rate of 25 g ha(-1) against cotton aphid (Aphis gossypii Glover) outperformed acetamiprid (25 g ha(-1) ) and dicrotophos (560 g ha(-1) ). Sulfoxaflor (50 g ha(-1) ) provided a control of sweetpotato whitefly equivalent to that of acetamiprid (75 g ha(-1) ) and imidacloprid (50 g ha(-1) ) and better than that of thiamethoxam (50 g ha(-1) ). CONCLUSION The novel chemistry of sulfoxaflor, its unique biological spectrum of activity and its lack of cross-resistance highlight the potential of sulfoxaflor as an important new tool for the control of sap-feeding insect pests.

Comparative inhibition of the juvenile hormone esterases from Trichoplusia ni, Tenebrio molitor, and Musca domestica

Abstract Twenty-seven compounds were screened as potential inhibitors of juvenile hormone esterases. Of these compounds O -ethyl- S -phenyl phosphoramidothiolate provided the best inhibition for the cabbage looper, Trichoplusia ni (Hubner), and the yellow mealworm, Tenebrio molitor L., while the juvenile hormone esterases of the house fly, Musca domestica L., were best inhibited by a juvenoid carbamate (1-( m -phenoxy- N -ethyl carbamate)-3,7-dimethyl-7-methoxy-2 E -octene). The inhibition patterns of T. ni and T. molitor are similar, while those of M. domestica are relatively different. Further studies on the juvenile hormone and α-napthyl acetate esterases of T. ni showed that they could be differentially inhibited. Diisopropyl phosphorofluoridate and an alkyl trifluoromethyl ketone selectively inhibit the hydrolysis of α-naphthyl acetate and juvenile hormone, respectively, while O -ethyl- S -phenyl phosporamidothiolate inhibits both enzymes. The juvenile hormone esterases of T. ni also appear to be unique enzymes that are selective for juvenile-hormone-like molecules. The in vivo inhibition of T. ni juvenile hormone esterases by O -ethyl- S -phenyl phosphoramidothiolate slows the in vivo hydrolysis of juvenile hormone and results in delayed pupation and malformed larvae that resemble larval-pupal intermediates. Thus, the esterases involved in juvenile hormone metabolism appear to be important in juvenile hormone regulation.

Sulfoxaflor and the sulfoximine insecticides: chemistry, mode of action and basis for efficacy on resistant insects.

The sulfoximines, as exemplified by sulfoxaflor ([N-[methyloxido[1-[6-(trifluoromethyl)-3-pyridinyl]ethyl]-λ(4)-sulfanylidene] cyanamide] represent a new class of insecticides. Sulfoxaflor exhibits a high degree of efficacy against a wide range of sap-feeding insects, including those resistant to neonicotinoids and other insecticides. Sulfoxaflor is an agonist at insect nicotinic acetylcholine receptors (nAChRs) and functions in a manner distinct from other insecticides acting at nAChRs. The sulfoximines also exhibit structure activity relationships (SAR) that are different from other nAChR agonists such as the neonicotinoids. This review summarizes the sulfoximine SAR, mode of action and the biochemistry underlying the observed efficacy on resistant insect pests, with a particular focus on sulfoxaflor.

Induction and regulation of juvenile hormone esterases during the last larval instar of the cabbage looper, Trichoplusia ni

Juvenile hormone esterase titres were monitored in gate I and gate II last instar larvae of Trichoplusia ni using JH 111 as substrate. Two peaks of activity were observed for both gate 1 and gate II larvae. although the first and second juvenile hormone esterase peaks for the gate II larvae are extended and delayed one day. respectively. Head or thoracic ligations before the prepupal stage lower or block the appearance of both esterase peaks. Juvenile hormone 1 and Ii. as well as homo and dihomo juvenoids can induce the second juvenile hormone esterase peak in both normal and ligated larvae, and increase the esterase titre during the first peak in nonligated larvae. Induction of the juvenile hormone esterases is possible in non-ligated larvae as soon as the moult to the last instar has occurred and in ligated larvae as soon as the first esterase peak has started to decline. Distinct mechanisms of regulation are present for the first and second juvenile hormone esterase peaks. Juvenile hormone does not appear to be involved in regulating its own metabolism by directly inducing the first esterase peak: however. evidence isconsistent with a brief burst of juvenile hormone which occurs prior to pupation inducing the production of the second peak of juvenile hormone esterase activity. KPI. Word Imkz: Trichoplusia ni. juvenile hormone. juvenoids. anti-juvenile hormone, juvenile hormone esterase, juvenile hormone-regulation. induction-juvenile hormone esterase, ecdysone.

The distribution of juvenile hormone esterase and its interrelationship with other proteins influencing juvenile hormone metabolism in the cabbage looper, Trichoplusia ni

Juvenile hormone esterase activity has been found in the haemolymph as well as fat body and midgut cytosolic subcellular fractions of last larval instar Trichoplusia ni. Isoelectric focusing and inhibitor studies were unable to distinguish the esterase activities in the haemolymph and fat body, while the midgut activity had a different isoelectric point and was more susceptible to inhibition. In addition, the haemolymph and fat body displayed similar patterns of juvenile hormone esterase activity during development in the last larval instar which were completely unlike that seen in the midgut. R-20458 epoxide hydrolase activity in the fat body and midgut peaks during the late feeding/early wandering stage of the last instar, as does haemolymph JH I binding activity. Since the rate of epoxide hydration is much lower than maximal rates of juvenile hormone esterase activity and the fluctuations in JH binding activity during development are relatively small, their influence on juvenile hormone turnover may be less important than metabolism by juvenile hormone esterase. Juvenile hormone esterase activity can be induced to appear synchronously in the haemolymph and fat body of newly-moulted pupae by topical application of the juvenoid epofen0nane. The accumulated evidence is consistent with the fat body serving as a source of the haemolymph juvenile hormone esterase. Key Word Index: Juvenile hormone esterase, inhibition, isoelectric focusing, induction, JH binding activity, epoxide hydrolase, Trichoplusia hi, trifluoromethyl ketone, phosphoramidothiolate

Natural products for pest control: an analysis of their role, value and future

Natural products (NPs) have long been used as pesticides and have broadly served as a source of inspiration for a great many commercial synthetic organic fungicides, herbicides and insecticides that are in the market today. In light of the continuing need for new tools to address an ever-changing array of fungal, weed and insect pests, NPs continue to be a source of models and templates for the development of new pest control agents. Interestingly, an examination of the literature suggests that NP models exist for many of the pest control agents that were discovered by other means, suggesting that, had circumstances been different, these NPs could have served as inspiration for the discovery of a great many more of todays pest control agents. Here, an attempt is made to answer questions regarding the existence of an NP model for existing classes of pesticides and what is needed for the discovery of new NPs and NP models for pest control agents.