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]-λ⁴-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.     

Effects of mutations in Drosophila nicotinic acetylcholine receptor subunits on sensitivity to insecticides targeting nicotinic acetylcholine receptors

Several strains of Drosophila melanogaster possess mutant alleles in nicotinic acetylcholine receptor (nAChR) subunits, Dα1 and Dβ2 that confer resistance to neonicotinoids such as imidacloprid and nitenpyram, and Dα6, that confers resistance to spinosyns. These mutant strains were bioassayed with a selected set of nAChR active insecticides including neonicotinoids, spinosad, and sulfoxaflor, a new sulfoximine insecticide. All of the neonicotinoids examined, except dinotefuran showed reduced insecticidal efficacy on larvae of the Dα1 mutant, suggesting that this subunit may be important in the action of these insecticides. All of the neonicotinoids, including dinotefuran, showed reduced insecticidal efficacy on larvae possessing the Dβ2 mutation. A similar pattern of broad neonicotinoid resistance to that of Dβ2 alone was also observed for larvae with both the mutations (Dα1 + Dβ2). The Dβ2 mutation exhibited a lower level of cross-resistance to sulfoxaflor (<3-fold) than to any of the neonicotinoids (>13-fold). In contrast, there was no cross-resistance for any of the neonicotinoids or sulfoxaflor in adult flies with the Dα6 mutation, which confers high levels of resistance to spinosad. Thus in the D. melanogaster strains studied, target site resistance observed for the neonicotinoids and the spinosyns does not translate directly to resistance towards sulfoxaflor.     

亚致死剂量氟啶虫胺腈对灰飞虱细胞色素P450的影响

为明确氟啶虫胺腈对灰飞虱Laodelphax striatellus细胞色素P450的影响,评估其抗药性风险,采用点滴法、酶活力分析法和实时荧光定量PCR法分别测定了氟啶虫胺腈对灰飞虱的毒性及对其细胞色素P450酶活力和P450基因表达量的影响。结果表明,氟啶虫胺腈对灰飞虱的致死中量LD_(50)随着虫龄的增加而升高,1~5龄若虫的LD_(50)为0.10~0.94 ng/头,雌、雄成虫的LD_(50)分别为1.09 ng/头和1.07 ng/头。氟啶虫胺腈对4龄若虫的亚致死剂量LD_(10)、LD_(30)和LD_(50)分别为0.17、0.41、0.76 ng/头,处理灰飞虱4龄若虫后可将其体内P450酶活力分别显著提高1.60、1.97和1.22倍;而各处理响应的P450基因的种类和数量不同,但相对表达量均受到诱导;CYP4DE1、CYP426A1、CYP303A1、CYP4C、CYP6FK1和CYP4C71v2的相对表达量表现出时间效应,表达量高峰在处理后24 h或48 h。表明不同亚致死剂量的氟啶虫胺腈在特定时间点可提高相应的细胞色素P450基因表达量,从而使酶蛋白量增加,可能导致灰飞虱体内细胞色素P450酶活力上升。     

新烟碱类杀虫剂吡虫啉和噻虫嗪的代谢研究进展

对新烟碱类杀虫剂吡虫啉和噻虫嗪的化学结构特点及代谢研究进展进行了综述,重点对其在哺乳动物、植物和昆虫体内的代谢途径及相关的生物代谢酶进行了阐述。吡虫啉和噻虫嗪在环境中可被动物、植物、微生物及昆虫所代谢,与其生物代谢相关的酶主要是微粒体细胞色素P450同工酶和醛氧化酶,其中,P450同工酶可催化吡虫啉和噻虫嗪发生羟基化、去饱和、脱烷基、硝基还原等代谢反应,而醛氧化酶主要催化其硝基部分的还原。吡虫啉和噻虫嗪经过代谢后其生物活性通常有所降低,但也有部分代谢产物的活性反而升高,增加了其对昆虫的毒性以及对非靶标生物的风险。明确吡虫啉和噻虫嗪的代谢途径、代谢产物及其生物活性,对于了解新烟碱类杀虫剂的代谢机理,以及安全有效地使用该类杀虫剂具有重要意义。     

褐飞虱对氟啶虫胺腈的抗性监测与生化抗性机制

为明确我国褐飞虱田间种群对氟啶虫胺腈的抗性现状及生化抗性机制,2017年-2019年采用稻茎浸渍法测定了采集自7省共13个褐飞虱田间种群对氟啶虫胺腈的抗性,并研究了氟啶虫胺腈抗性种群与其他杀虫剂的交互抗性以及增效剂对氟啶虫胺腈的增效效果。结果表明：近3年来褐飞虱对氟啶虫胺腈产生了中等水平抗性(RR=10.3～30.9)。氟啶虫胺腈抗性品系对呋虫胺、噻虫嗪和烯啶虫胺分别产生了9.1倍、7.9倍和4.1倍的低水平交互抗性,与噻嗪酮、毒死蜱、吡蚜酮、三氟苯嘧啶和吡虫啉不存在交互抗性。增效剂PBO对氟啶虫胺腈抗性品系和浙江龙游19(Longyou-19)田间种群分别具有4.2倍和3.8倍的明显增效作用。综上,褐飞虱田间种群已对氟啶虫胺腈产生中等水平抗性。多功能氧化酶参与了褐飞虱对氟啶虫胺腈的代谢抗性。     

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. Copyright © 2010 Society of Chemical Industry     

Genetic and biochemical mechanisms limiting fipronil toxicity in the LPR strain of house fly,Musca domestica

Fipronil is a new insecticide which exerts its toxic action by interacting with the insect GABA-gated chloride channel. Previous studies have shown that cyclodiene-resistant insects have low to moderate levels of cross-resistance to fipronil, while other resistant strains are usually susceptible. In contrast, we recently found a strain (LPR) of house fly (Musca domestica L) with 15-fold cross-resistance to fipronil that was not associated with cyclodiene resistance. Fipronil cross-resistance in LPR was inherited as an intermediately dominant, autosomal, multigenic trait. [¹⁴C]Fipronil was observed to penetrate into LPR flies more slowly than into susceptible flies. S,S,S-tributylphosphorotrithioate and diethyl maleate pretreatment did not reduce the level of fipronil cross-resistance, while piperonyl butoxide resulted in a slight decrease. These results indicate that decreased penetration and monooxygenase-mediated detoxification may be mechanisms contributing to fipronil cross-resistance in the LPR strain. © 1999 Society of Chemical Industry     

Spinosad resistance in female Musca domestica L. from a field-derived population

BACKGROUND: Bait-formulated spinosad is currently being introduced for housefly (Musca domestica L.) control around the world. Spinosad resistance was evaluated in a multiresistant field population and strains derived from this by selection with insecticides. Constitutive and spinosad-induced expression levels of three cytochrome P450 genes, CYP6A1, CYP6D1 and CYP6D3, previously reported to be involved in insecticide resistance, were examined. RESULTS: In 2004 a baseline for spinosad toxicity of Danish houseflies where all field populations were considered to be susceptible was established. In the present study, females of a multiresistant field population 791a were, however, 27-fold spinosad resistant at LC₅₀, whereas 791a male houseflies were susceptible. Strain 791a was selected with spinosad, thiamethoxam, fipronil and imidacloprid, resulting in four strains with individual characteristics. Selection of 791a with spinosad did not alter spinosad resistance in either males or females, but counterselected against resistance to the insecticides thiamethoxam and imidacloprid targeting nicotinic acetylcholine receptors. A synergist study with piperonyl butoxide, as well as gene expression studies of CYP6A1, CYP6D1 and CYP6D3, indicated a partial involvement of cytochrome P450 genes in spinosad resistance. CONCLUSION: This study reports female-linked spinosad resistance in Danish houseflies. Negative cross-resistance was observed between spinosad and neonicotinoids in one multiresistant housefly strain. Spinosad resistance involved alterations of cytochrome P450 gene expression. Copyright © 2011 Society of Chemical Industry     

Homology modelling of Drosophila cytochrome P450 enzymes associated with insecticide resistance

BACKGROUND: Overexpression of the cytochrome P450 gene Cyp6g1 confers resistance against DDT and a broad range of other insecticides in Drosophila melanogaster Meig. In the absence of crystal structures of CYP6G1 or complexes with its substrates, structural studies rely on homology modelling and ligand docking to understand P450–substrate interactions. RESULTS: Homology models are presented for CYP6G1, a P450 associated with resistance to DDT and neonicotinoids, and two other enzymes associated with insecticide resistance in D. melanogaster, CYP12D1 and CYP6A2. The models are based on a template of the X‐ray structure of the phylogenetically related human CYP3A4, which is known for its broad substrate specificity. The model of CYP6G1 has a much smaller active site cavity than the template. The cavity is also ‘V’‐shaped and is lined with hydrophobic residues, showing high shape and chemical complementarity with the molecular characteristics of DDT. Comparison of the DDT–CYP6G1 complex and a non‐resistant CYP6A2 homology model implies that tight‐fit recognition of this insecticide is important in CYP6G1. The active site can accommodate differently shaped substrates ranging from imidacloprid to malathion but not the pyrethroids permethrin and cyfluthrin. CONCLUSION: The CYP6G1, CYP12D1 and CYP6A2 homology models can provide a structural insight into insecticide resistance in flies overexpressing P450 enzymes with broad substrate specificities. Copyright © 2010 Society of Chemical Industry     

Species differences in chlorantraniliprole and flubendiamide insecticide binding sites in the ryanodine receptor

Anthranilic and phthalic diamides exemplified by chlorantraniliprole (Chlo) or cyantraniliprole (Cyan) and flubendiamide (Flu), respectively, are the newest major chemotype of insecticides with outstanding potency, little or no cross resistance with other classes and low mammalian toxicity. They are activators of the ryanodine (Ry) receptor (RyR)-Ca²⁺ channel, based on Ca²⁺ flux and electrophysiology investigations. The goal of this study is to define species differences in the degree and mechanisms of diamide selective action by radioligand specific binding studies at the [³H]Ry, [³H]Chlo and [³H]Flu sites. The [³H]Ry site is observed in muscle of lobster, rabbit and four insect species (Musca domestica, Apis mellifera, Heliothis virescens and Agrotis ipsilon) whereas the [³H]Chlo site is evident in the four insects and the [³H]Flu site in only the two lepidoptera (Agrotis and Heliothis). [³H]Ry binding is significantly stimulated by Chlo, Cyan and Flu with the insects (except Flu with Musca) but not the lobster and rabbit. [³H]Chlo binding is stimulated by Ry and Flu in Musca and Apis but not in the lepidoptera, while Flu and Cyan are inhibitory. [³H]Flu binding is strongly inhibited by Chlo and Cyan in Agrotis and Heliothis. [³H]Chlo and [³H]Flu binding are not dependent on added Ca²⁺ or ATP in Heliothis and Agrotis whereas the other radioligand-receptor combinations are usually enhanced by Ca²⁺ and ATP. More generally, there are species differences in the Ry, Chlo and Flu binding sites of the RyR that may confer selective toxicity and determine target site cross resistance mechanisms.     

我国棉蚜对吡虫啉和氟啶虫胺腈抗性水平监测与交互抗性分析

为了解我国不同地区棉蚜Aphis gossypii对吡虫啉和氟啶虫胺腈的抗性现状,对代表性棉区棉蚜田间种群进行抗药性监测,同时通过构建具有R81T及V62I单突变和R81T-V62I共同突变的棉蚜烟碱型乙酰胆碱受体（nicotinic acetylcholine receptor,nAChR）蛋白模型,与吡虫啉和氟啶虫胺腈进行分子对接,分析这些突变在吡虫啉和氟啶虫胺腈抗性中的作用,并分析吡虫啉和氟啶虫胺腈之间是否存在交互抗性。结果显示,不同地区棉蚜对吡虫啉产生了高水平抗性,抗性倍数为174.70~56 409.18,对氟啶虫胺腈产生了低至中等水平抗性,抗性倍数为7.35~44.63,说明不同地区的棉蚜对氟啶虫胺腈的敏感度高于吡虫啉,且吡虫啉抗性和氟啶虫胺腈抗性间不存在相关性。R81T、V62I单突变和R81T-V62I共同突变导致吡虫啉与棉蚜nAChR的亲和力降低,对氟啶虫胺腈与棉蚜nAChR的结合无明显影响。R81T及V62I单突变和R81T-V62I共同突变导致棉蚜对吡虫啉产生靶标抗性,但是对氟啶虫胺腈的抗性无明显影响,这些突变不会导致吡虫啉与氟啶虫胺腈产生靶标突变的交互抗性。     

Thiamethoxam is a neonicotinoid precursor converted to clothianidin in insects and plants

Neonicotinoid insecticides are compounds acting agonistically on insect nicotinic acetylcholine receptors (nAChR). They are especially active on hemipteran pest species such as aphids, whiteflies, and planthoppers, but also commercialized to control many coleopteran and some lepidopteran pest species. The most prominent member of this class of insecticides is imidacloprid. All neonicotinoid insecticides bind with high affinity (I₅₀-values around 1 nM) to [³H]imidacloprid binding sites on insect nAChRs. One notable ommission is the neonicotinoid thiamethoxam, showing binding affinities up to 10,000-fold less potent than the others, using housefly head membrane preparations. Electrophysiological whole cell voltage clamp studies using neurons isolated from Heliothis virescens ventral nerve cord showed no response to thiamethoxam when applied at concentrations of 0.3 mM, although the symptomology of poisoning in orally and topically treated noctuid larvae suggested strong neurotoxicity. Other neonicotinoids, such as clothianidin, exhibited high activity as agonists on isolated neurons at concentrations as low as 30 nM. There was no obvious correlation between biological efficacy of thiamethoxam against aphids and lepidopterans and receptor affinity in electrophysiological and binding assays. Pharmacokinetic studies using an LC-MS/MS approach to analyze haemolymph samples taken from lepidopteran larvae revealed that thiamethoxam orally applied to 5th instar Spodoptera frugiperda larvae was rapidly metabolized to clothianidin, an open-chain neonicotinoid. Clothianidin shows high affinity to nAChRs in both binding assays and whole cell voltage clamp studies. When applied to cotton plants, thiamethoxam was also quickly metabolized, with clothianidin being the predominant neonicotinoid in planta briefly after application, as indicated by LC-MS/MS analyses. Interestingly, the N-desmethylated derivative of thiamethoxam, N-desmethyl thiamethoxam, was not significantly produced in either lepidopteran larvae or in cotton plants, although it was often mentioned as a possible metabolite, being nearly as active as imidacloprid. In conclusion, our investigations show that thiamethoxam is likely to be a neonicotinoid precursor for clothianidin.     

Imidacloprid‐susceptible Nilaparvata lugens individuals exceeded resistant individuals in a mixture population with density pressure

BACKGROUND

Fitness costs associated with insecticide resistance in pest insects have mainly been studied under optimal laboratory conditions. However, resistant insects face more stressors than just insecticides in the field, and how the resistant population reacts to these stressors is of practical importance for the control of pest insects such as the brown planthopper Nilaparvata lugens. The aim of the present study was to explore the impact of population density on the competitiveness of resistant and susceptible individuals.

RESULTS

Two isogenic N. lugens populations, a highly imidacloprid‐resistant population (HZ‐R) with a resistance ratio (RR) of 227.10 and a relatively susceptible population (HZ‐S) with an RR of 2.99, were created from a field‐resistant population (HZ; RR 62.51). The high resistance levels of HZ‐R and HZ were mainly attributable to the overexpression of multiple cytochrome P450 (CYP) genes such as CYP6ER1, CYP6AY1, CYP6CW1 and CYP4CE1 compared with HZ‐S, this being supported by piperonyl butoxide synergism. HZ‐R was observed to be more resistant to thiacloprid and etofenprox compared with HZ and HZ‐S. Most interestingly, in high population density treatments, HZ‐S individuals were much more competitive than HZ‐R individuals.

CONCLUSION

Imidacloprid‐resistant individuals of N. lugens are less competitive than their susceptible counterparts under density pressure. © 2017 Society of Chemical Industry     

N-氰基甲基-[(苯甲酰基)(2-氯噻唑-5-基甲基)氨基乙基]砜亚胺类化合物的合成及杀虫活性

为了寻找和发现高效、广谱、低毒、低生态风险并与现有杀虫剂无交互抗性的新型杀虫剂,以2-氯-5-氯甲基噻唑为原料,经多步反应制得10个新型N-氰基甲基 砜亚胺类化合物,其结构均经核磁共振氢谱、元素分析确证。室内生物活性测试结果表明,目标化合物对桃蚜Myzus persicae具有一定的杀虫活性,其中化合物 7-1 在质量浓度为10 mg/L下对桃蚜的致死率达到80%。     

Metabolism of O,O-dimethyl S-[α-carboethoxy)benzyl]phosphorodithioate (phenthoate) in the white mouse and house flies

The metabolism of O,O-dimethyl S-[α-(carboethoxy)benzyl]phosphorodithioate (phenthoate), an organophosphorus insecticide of low mammalian toxicity, was investigated in white mice and in susceptible and resistant strains of house flies. Phenthoate was metabolized rapidly in the mouse to a wide variety of detoxication products and only an insignificant amount of phenthoate oxon was detected. The same detoxication products were produced in house flies but, compared to the mouse, substantial amounts of phenthoate oxon also were found. The selective toxicity of phenthoate between insect and mammal is attributable to the difference in the accumulation of the oxon.     

Investigating nicotinic acetylcholine receptor expression in neonicotinoid resistant Myzus persicae FRC

The peach–potato aphid Myzus persicae is a pest of many commercial crops due to its polyphagous nature of feeding and has a well-documented history of acquiring resistance to insecticides. In 2009 a strain (M. persicae FRC) emerged in southern France with a point mutation (R81T) at the nicotinic acetylcholine receptor (nAChR), the target site for neonicotinoids such as imidacloprid. This point mutation was associated with the loss of the high affinity imidacloprid binding site (pM Kd), with the single remaining binding site (low nM Kd) highly overexpressed compared to laboratory controls (Bass et al., 2011 [1]). Here we report that after 2 years of continuous selection in the glass house environment with neonicotinoids, the total level of IMD-sensitive nAChRs (low nM Kd) in M. persicae FRC is now comparable to laboratory controls (pM and low nM Kd). Interestingly, despite this large reduction in IMD-sensitive nAChRs, this was not associated with any significant alteration in NNIC-lethality. Additionally, sustained absence of neonicotinoid-selection did not alter nAChR protein levels. We suggest that alterations in nAChR protein expression level described in the original characterisation of the field-isolated M. persicae FRC is unlikely to have been a direct consequence of the R81T mutation. Rather, we speculate that nAChR expression in aphids is likely influenced by as yet unknown conditions in the natural field environment that are absent in the laboratory setting.     

Herbicide resistance in transgenic plants with mammalian P450 monooxygenase genes

Transgenic potato and rice plants were generated by the introduction of human P450 species, CYP1A1, CYP2B6, CYP2C9 and CYP2C19, which metabolized a number of herbicides, insecticides and industrial chemicals. The transgenic potato plant T1977 co-expressing CYP1A1, CYP2B6 and CYP2C19 genes showed remarkable cross-resistance to several herbicides with different structures and modes of action due to metabolism of these herbicides by the P450 species expressed. The transgenic rice plant 2C9-57R2 expressing CYP2C9 gene showed resistance to sulfonylureas, and the transgenic rice plant 2C19-12R1 expressing CYP2C19 gene showed cross-resistance to certain herbicides with different structures and modes of action. These transgenic plants appear to be useful for herbicide resistance as well as phytoremediation of environmental contaminants.     

Two cytochrome P450 genes are involved in imidacloprid resistance in field populations of the whitefly, Bemisia tabaci, in China

The sweet potato whitefly, Bemisia tabaci (Gennadius) (Hemiptera:Aleyrodidae), is an invasive and damaging pest of field crops worldwide. The neonicotinoid insecticide imidacloprid has been widely used to control this pest. We assessed the species composition (B vs. Q), imidacloprid resistance, and association between imidacloprid resistance and the expression of five P450 genes for 14–17 B. tabaci populations in 12 provinces in China. Fifteen of 17 populations contained only B. tabaci Q, and two populations contained both B and Q. Seven of 17 populations exhibited moderate to high resistance to imidacloprid, and eight populations exhibited low resistance to imidacloprid, compared with the most susceptible field WHHB population. In a study of 14 of the populations, resistance level was correlated with the expression of the P450 genes CYP6CM1 and CYP4C64 but not with the expression of CYP6CX1, CYP6CX4, or CYP6DZ7. This study indicates that B. tabaci Q has a wider distribution in China than previously reported. Resistance to imidacloprid in field populations of B. tabaci is associated with the increased expression of two cytochrome P450 genes (CYP6CM1 and CYP4C64).     

Resistance and cross-resistance to the spinosyns - A review and analysis

The spinosyns were introduced in 1997 with the launch of spinosad. Since then, there have been several cases of resistance to spinosad in the field populations of insect pest species that have resulted in reduced efficacy. There have also been a number of studies where spinosad-resistant insect strains were created and characterized in the laboratory. Likewise many studies examining resistance to a variety of other classes of insecticides have included spinosad in the evaluation of their cross-resistance spectrum. Understanding mechanisms of resistance and cross-resistance can provide the basis for developing insecticide resistance management programs, as well as defining the most appropriate tools to address potential resistance issues. This review provides an overview and analysis of resistance and cross-resistance to the spinosyns (spinosad and spinetoram). Although there are more than 30 examples of resistance to the spinosyns, only half of these are related to selection in the field. The majority of these field selected examples occur in either the diamondback moth or western flower thrips. There have also been over 85 studies investigating cross-resistance to the spinosyns. However, in half of these studies spinosad showed no cross-resistance, and in another third of the total studies spinosad cross-resistance was minimal. Therefore, while resistance and cross-resistance to the spinosyns does occur, it is appears to be more limited in impact than might be implied from the large body of literature on the subject.