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Novel and viable acetylcholinesterase target site for developing effective and environmentally safe insecticides.

ABSTRACT: Insect pests are responsible for human suffering and financial losses worldwide. New and environmentally safe insecticides are urgently needed to cope with these serious problems. Resistance to current insecticides has resulted in a resurgence of insect pests, and growing concerns about insecticide toxicity to humans discourage the use of insecticides for pest control. The small market for insecticides has hampered insecticide development; however, advances in genomics and structural genomics offer new opportunities to develop insecticides that are less dependent on the insecticide market. This review summarizes the literature data that support the hypothesis that an insect-specific cysteine residue located at the opening of the acetylcholinesterase active site is a promising target site for developing new insecticides with reduced off-target toxicity and low propensity for insect resistance. These data are used to discuss the differences between targeting the insect-specific cysteine residue and targeting the ubiquitous catalytic serine residue of acetylcholinesterase from the perspective of reducing off-target toxicity and insect resistance. Also discussed is the prospect of developing cysteine-targeting anticholinesterases as effective and environmentally safe insecticides for control of disease vectors, crop damage, and residential insect pests within the financial confines of the present insecticide market.

SUBMITTER: Pang YP

PROVIDER: S-EPMC3343382 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Novel and viable acetylcholinesterase target site for developing effective and environmentally safe insecticides.

Pang Yuan-Ping YP Brimijoin Stephen S Ragsdale David W DW Zhu Kun Yan KY Suranyi Robert R

Current drug targets 20120401 4

Insect pests are responsible for human suffering and financial losses worldwide. New and environmentally safe insecticides are urgently needed to cope with these serious problems. Resistance to current insecticides has resulted in a resurgence of insect pests, and growing concerns about insecticide toxicity to humans discourage the use of insecticides for pest control. The small market for insecticides has hampered insecticide development; however, advances in genomics and structural genomics of ...[more]

PMID: 22280344

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Project description:The use of fungicides in agriculture has been playing a role in the enhancement of agricultural yields through the control of pathogens causing serious diseases in crops. Still, adverse environmental and human health effects resulting from its application have been reported. In this study, the possibility of readjusting the formulation of a commercial product combining azoxystrobin and tebuconazole (active ingredients - AIs; Custodia®) towards environmentally safer alternative(s) was investigated. Specifically, the sensitivity of non-target aquatic communities to each AI was first evaluated by applying the Species Sensitivity Distributions (SSDs) approach. Then, mixtures of these AIs were tested in a non-target organism (Raphidocelis subcapitata) denoting sensitivity to both AIs as assessed from SSDs. The resulting data supported the design of the last stage of this study, where mixtures of those AIs at equivalent vs. alternative ratios and rates as in the commercial formulation were tested against two target fungal species: Pyrenophora teres CBS 123929 and Rhynchosporium secalis CBS 110524. The comparison between the sensitivity of non-target aquatic species and the corresponding efficacy towards target fungi revealed that currently applied mixture and rates of these AIs are generally environmentally safe (antagonistic interaction; concentrations below the EC1 for R. subcapitata and generally below the HC5 for aquatic non-target communities), but ineffective against target organisms (maximum levels of inhibition of 70 and 50% in P. teres CBS 123929 and R. secalis CBS 110524, respectively). Results additionally suggest a potentiation of the effects of the AIs by the other formulants added to the commercial product at tested rates. Overall, this study corroborates that commercial products can be optimized during design stages based on a systematic ecotoxicological testing for ingredient interactions and actual efficacy against targets. This could be a valuable pathway to reduce environmental contamination during transition to a more sustainable agricultural production.

Project description:BackgroundIn the final phase of China's national programme to eliminate malaria by 2020, it is vitally important to monitor the resistance of malaria vectors for developing effective vector control strategies. In 2017 Shanghai declared that it had eliminated malaria; however, the insecticide resistance status of the primary malaria vector Anopheles sinensis remains unknown.MethodsWe examined the pyrethroid and organophosphate resistance of An. sinensis via a bioassay of two populations from the Chongming District of Shanghai. The voltage-gated sodium channel (VGSC) and acetylcholinesterase 1 (ace-1) genes were partially sequenced to examine the association between resistance phenotype and target site genotype. In addition, the geographical distribution, polymorphism and genotype frequencies of insecticide resistance genes were examined using samples collected during routine mosquito surveillance in 2016 and 2017 from Chongming, Songjiang, Jiading and Qingpu Districts.ResultsIn Chongming District, the An. sinensis population near Dongtan National Nature Reserve showed resistance to pyrethroids, sensitivity to organophosphate, no knockdown resistance (kdr) mutations in the VGSC gene, and a low frequency (1.71%) of the ace-1 119S allele. An An. sinensis population near the Chongming central area (CM-Xinhe population) showed high resistance to pyrethroids and organophosphates and high frequencies of kdr 1014F and 1014C (80.73%) and ace-1 119S (85.98%) alleles. A significant association was detected between the homozygous kdr mutation 1014F/1014F and pyrethroid resistance in the CM-Xinhe population, indicating that the kdr mutation is probably recessive. Eight kdr genotypes with 1014F and 1014C substitutions were detected in the four surveyed districts of Shanghai. TTT and GGC/AGC were the dominant kdr allele and ace-1 genotype, respectively, and were prevalent in most Shanghai An. sinensis populations.ConclusionsOn the basis of our assessment of insecticide resistance gene mutations in Shanghai, we identified a kdr mutation-free population in Chongming Dongtan. However, high frequencies of target-site mutations of insecticide resistance genes were observed in most areas of Shanghai. Bioassays of An. sinensis populations in the central Chongming District indicated the high insecticide resistance status of An. sinensis populations in Shanghai. We accordingly recommend a restriction on insecticide usage and development of effective integrated pest/vector management interventions to support disease control efforts.

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Novel and viable acetylcholinesterase target site for developing effective and environmentally safe insecticides.

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Novel and viable acetylcholinesterase target site for developing effective and environmentally safe insecticides.

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