metaflumizone and indoxacarb

Sodium channel blocker insecticides (SCBIs) are a relatively new class of insecticides that are represented by two commercially registered compounds, indoxacarb and metaflumizone. SCBIs, like pyrethroids and DDT, target voltage-gated sodium channels (VGSCs) to intoxicate insects. In contrast to pyrethroids, however, SCBIs inhibit VGSCs at a distinct receptor site that overlaps those of therapeutic inhibitors of sodium channels, such as local anesthetics, anticonvulsants and antiarrhythmics. This review will recount the development of the SCBI insecticide class from its roots as chitin synthesis inhibitors, discuss the symptoms of poisoning and evidence supporting inhibition of VGSCs as their mechanism of action, describe the current model for SCBI-induced inhibition of VGSCs, present a model for the receptor for SCBIs on VGSCs, and highlight differences between data collected from mammalian and insect experimental models.

Topics: Action Potentials; Animals; Humans; Insecticides; Oocytes; Oxazines; Semicarbazones; Sodium Channel Blockers; Voltage-Gated Sodium Channels; Xenopus

Despite investment in programs to manage the development of resistance to existing agents, this continues to drive the need for discovery of novel antiparasitic agents for veterinary medicine. Historically, antiparasitic drug discovery was driven by empirical screening, but technological advances have lead to an increased focus on mechanism-based approaches to drug discovery and this is projected to increase as our capabilities advance to improve both the throughput of assays and the quality of data generated. Investment in the development of combination products with novel agents is increasing and, despite regulatory hurdles in some regions, efforts to globally harmonize regulations will aid in delivering safe, efficacious drugs to help in resistance management and integrated parasite control programs.

Topics: Aminoacetonitrile; Animals; Antiparasitic Agents; Drug Combinations; Drug Discovery; Macrolides; Oxazines; Semicarbazones; Veterinary Drugs

The fall armyworm (FAW), Spodoptera frugiperda is the main destructive pest of grain crops, and has led to substantial economic losses worldwide. Chemical pesticides are the most effective way to manage FAW. Here, a laboratory test using an artificial diet-incorporated assay was conducted to determine the toxicity of five insecticides and the joint effect of the binary combination insecticides to FAW larvae. A field plot test using foliar spray was carried out to assess the control efficacy of metaflumizone mixed with chlorantraniliprole or indoxacarb against FAW.. The bioassay results showed that metaflumizone had a stronger insecticidal effect than indoxacarb toward FAW larvae. Furthermore, the mixture of metaflumizone and chlorantraniliprole in a volume ratio of 3:7 had the strongest synergistic effect against FAW, with a co-toxicity coefficient (CTC) of 317.18. The best synergistic effect for mixtures of metaflumizone and indoxacarb was observed at a 1:9 volume ratio, with a CTC of 185.98. However, there was an antagonistic effect of metaflumizone mixed with emamectin benzoate and with lufenuron, because the co-toxic factor was less than -20 at volume ratios of 8:2 and 9:1, respectively. According to the results of the field trial, metaflumizone mixed with chlorantraniliprole or indoxacarb at a 50% reduction of the application rate can effectively control FAW with efficacy ranging from 77.73% to 94.65% 1-7 days postapplication.. Overall, our findings suggest that metaflumizone and its binary combination insecticides can be utilized in FAW integrated pest management programs. © 2022 Society of Chemical Industry.

Topics: Animals; Insecticide Resistance; Insecticides; Larva; Spodoptera

Sodium channel blocker insecticides (SCBIs) like indoxacarb and metaflumizone offer an alternative insecticide resistance management (IRM) strategy against several pests that are resistant to other compounds. However, resistance to SCBIs has been reported in several pests, in most cases implicating metabolic resistance mechanisms, although in certain indoxacarb resistant populations of Plutella xylostella and Tuta absoluta, two mutations in the domain IV S6 segment of the voltage-gated sodium channel, F1845Y and V1848I have been identified, and have been postulated through in vitro electrophysiological studies to contribute to target-site resistance. In order to functionally validate in vivo each mutation in the absence of confounding resistance mechanisms, we have employed a CRISPR/Cas9 strategy to generate strains of Drosophila melanogaster bearing homozygous F1845Y or V1848I mutations in the para (voltage-gated sodium channel) gene. We performed toxicity bioassays of these strains compared to wild-type controls of the same genetic background. Our results indicate both mutations confer moderate resistance to indoxacarb (RR: 6-10.2), and V1848I to metaflumizone (RR: 8.4). However, F1845Y confers very strong resistance to metaflumizone (RR: >3400). Our molecular modeling studies suggest a steric hindrance mechanism may account for the resistance of both V1848I and F1845Y mutations, whereby introducing larger side chains may inhibit metaflumizone binding.

Topics: Animals; Drosophila melanogaster; Drosophila Proteins; Gene Editing; Genome; Insecticide Resistance; Models, Molecular; Oxazines; Protein Domains; Semicarbazones; Sodium Channel Blockers; Sodium Channels

Indoxacarb and metaflumizone belong to a relatively new class of sodium channel blocker insecticides (SCBIs). Due to intensive use of indoxacarb, field-evolved indoxacarb resistance has been reported in several lepidopteran pests, including the diamondback moth Plutella xylostella, a serious pest of cruciferous crops. In particular, the BY12 population of P. xylostella, collected from Baiyun, Guangdong Province of China in 2012, was 750-fold more resistant to indoxacarb and 70-fold more resistant to metaflumizone compared with the susceptible Roth strain. Comparison of complementary DNA sequences encoding the sodium channel genes of Roth and BY12 revealed two point mutations (F1845Y and V1848I) in the sixth segment of domain IV of the PxNav protein in the BY population. Both mutations are located within a highly conserved sequence region that is predicted to be involved in the binding sites of local anesthetics and SCBIs based on mammalian sodium channels. A significant correlation was observed among 10 field-collected populations between the mutant allele (Y1845 or I1848) frequencies (1.7% to 52.5%) and resistance levels to both indoxacarb (34- to 870-fold) and metaflumizone (1- to 70-fold). The two mutations were never found to co-exist in the same allele of PxNav , suggesting that they arose independently. This is the first time that sodium channel mutations have been associated with high levels of resistance to SCBIs. F1845Y and V1848I are molecular markers for resistance monitoring in the diamondback moth and possibly other insect pest species.

Topics: Amino Acid Sequence; Animals; Base Sequence; Insecticide Resistance; Molecular Sequence Data; Moths; Mutation; Oxazines; Semicarbazones; Sodium Channel Blockers; Sodium Channels

Indoxacarb and metaflumizone are two sodium channel blocker insecticides (SCBIs). They preferably bind to and trap sodium channels in the slow-inactivated non-conducting state, a mode of action similar to that of local anesthetics (LAs). Recently, two sodium channel mutations, F1845Y (F(4i15)Y) and V1848I (V(4i18)I), in the transmembrane segment 6 of domain IV (IVS6), were identified to be associated with indoxacarb resistance in Plutella xylostella. F(4i15) is known to be critical for the action of LAs on mammalian sodium channels. Previously, mutation F(4i15)A in a cockroach sodium channel, BgNav1-1a, has been shown to reduce the action of lidocaine, a LA, but not the action of SCBIs. In this study, we introduced mutations F(4i15)Y and V(4i18)A/I individually into the cockroach sodium channel, BgNav1-1a, and conducted functional analysis of the three mutants in Xenopus oocytes. We found that both the F(4i15)Y and V(4i18)I mutations reduced the inhibition of sodium current by indoxacarb, DCJW (an active metabolite of indoxacarb) and metaflumizone. F(4i15)Y and V(4i18)I mutations also reduced the use-dependent block of sodium current by lidocaine. In contrast, substitution V(4i18)A enhanced the action metaflumizone and lidocaine. These results show that both F(4i15)Y and V(4i18)I mutations may contribute to target-site resistance to SCBIs, and provide the first molecular evidence for common amino acid determinants on insect sodium channels involved in action of SCBIs and LA.

Topics: Anesthetics, Local; Animals; Cockroaches; Insect Proteins; Insecticide Resistance; Insecticides; Lidocaine; Mutation; Oocytes; Oxazines; Protein Domains; Semicarbazones; Sodium Channel Blockers; Sodium Channels; Xenopus

Diamondback moth, Plutella xylostella (L.) is a serious insect pest of vegetables worldwide, and has evolved resistance to various kinds of insecticides. Studies were conducted to determine the baseline toxicity of metaflumizone and the possibility of cross-resistance between metaflumizone and indoxacarb, two sodium channel blocking insecticides (SCBIs), in field populations of P. xylostella from China. The variation in susceptibility to metaflumizone among 29 field populations of P. xylostella collected from 14 geographical locations in China was less than five-fold, with 50% lethal concentrations (LC50(s)) varying from 1.34 to 6.55 mg/liter. Limited variations in LC50(s) (less than five-fold, ranging from 1.76 to 8.16 mg/liter) were also observed in the four laboratory-selected strains with high levels of resistance to abamectin, spinosad, fipronil, or Bt toxin Cry1Ac. The toxicity of metaflumizone and indoxacarb was compared among 23 out of the 29 field populations. When compared with the susceptible Roth strain, the JN-09B population showed the highest level of resistance to indoxacarb (110-fold), but two-fold tolerance to metaflumizone. The other 22 populations (with 5- to 58-fold of resistance to indoxacarb) had 1- to three-fold tolerance to metaflumizone. Metaflumizone could provide an effective alternative insecticide for diamondback moth management. Although the field populations of P. xylostella tested with various levels of resistance to indoxacarb did not have cross-resistance to metaflumizone, metaflumizone should be rotated with other chemicals of different modes of action instead of indoxacarb.

Topics: Animals; Biological Assay; China; Dose-Response Relationship, Drug; Insecticide Resistance; Insecticides; Larva; Lethal Dose 50; Moths; Oxazines; Selection, Genetic; Semicarbazones

Sodium channel blocker insecticides (SCBIs), such as indoxacarb and metaflumizone, are a new class of insecticides with a mechanism of action different from those of other insecticides that target sodium channels. SCBIs block sodium channels in a manner similar to local anesthetics (LAs) such as lidocaine. Several residues, particularly F1579 and Y1586, in the sixth transmembrane segment (S6) of domain IV (IV) of rat Na(v)1.4 sodium channels are required for the action of LAs and SCBIs and may form part of overlapping receptor sites. However, the binding site for SCBIs in insect sodium channels remains undefined. We used site-directed mutagenesis, the Xenopus laevis oocyte expression system, and the two-electrode voltage clamp technique to study the effects on SCBI activity of mutating F1817 and Y1824 (analogous to those residues identified in mammalian sodium channels) to alanine, in the voltage-sensitive sodium channel of the German cockroach, Blattella germanica. The mutant channels showed no effect or a marked increase in channel sensitivity to both DCJW (the active metabolite of indoxacarb) and metaflumizone. Thus, it appeared that although the F1817 residue plays a role in the action of SCBIs and that both residues are involved in LA activity in mammalian sodium channels, neither F1817 nor Y1824 are integral determinants of SCBI binding on insect sodium channels. Our results suggest that the receptor site of SCBIs on insect sodium channels may be significantly different from that on mammalian sodium channels.

Topics: Animals; Cockroaches; Ion Channel Gating; Membrane Potentials; Mutagenesis, Site-Directed; Oocytes; Oxazines; Patch-Clamp Techniques; Phenylalanine; Protein Structure, Tertiary; Semicarbazones; Sodium Channel Blockers; Time Factors; Tyrosine; Xenopus laevis