Abstract
The introduction of neonicotinoids for managing insecticide resistance in mosquitoes is of high interest as they interact with a biochemical target not previously used in public health. In this concern, Bayer developed a combination of the neonicotinoid clothianidin and the pyrethroid deltamethrin (brand name Fludora Fusion) as a new vector control tool. Although this combination proved to be efficient against pyrethroid-resistant mosquitoes, its ability to prevent the selection of pyrethroid and neonicotinoid resistance alleles was not investigated. In this context, the objective of this work was to study the dynamics and the molecular mechanisms of resistance of An. gambiae to the separated or combined components of this combination. A field-derived An. gambiae line carrying resistance alleles to multiple insecticides at low frequencies was used as a starting for 33 successive generations of controlled selection. Resistance levels to each insecticide and target site mutation frequencies were monitored throughout the selection process. Cross resistance to other public health insecticides were also investigated. RNA-seq was used to compare gene transcription variations and polymorphisms across all lines. This study confirmed the potential of this insecticide combination to impair the selection of resistance as compared to its two separated components. Deltamethrin selection led to the rapid enrichment of the kdr L1014F target-site mutation. Clothianidin selection led to the over-transcription of multiple cytochrome P450s including some showing high homology with those conferring neonicotinoid resistance in other insects. A strong selection signature associated with clothianidin selection was also observed on a P450 gene cluster previously associated with resistance. Within this cluster, the gene CYP6M1 showed the highest selection signature together with a transcription profile supporting a role in clothianidin resistance. Modelling the impact of point mutations selected by clothianidin on CYP6M1 protein structure showed that selection retained a protein variant with a modified active site potentially enhancing clothianidin metabolism. In the context of the recent deployment of neonicotinoids for mosquito control and their frequent usage in agriculture, the present study highlights the benefit of combining them with other insecticides for preventing the selection of resistance and sustaining vector control activities.
Highlights
The introduction of neonicotinoids for managing insecticide resistance in mosquitoes is of high interest as they interact with a biochemical target not previously used in public health
Kdr mutations affecting malaria vectors are widely distributed in Africa with two distinct mutations at position 1014 of the voltage-gated sodium channel (VGSC) mainly associated with insecticide r esistance[10,11]: the L1014F kdr west mutation and the L1014S kdr east mutation[12,13]
Among the insecticides which are being proposed for managing pyrethroid resistance, neonicotinoids have aroused a high interest as (i) they have not previously been used for public health, (ii) they show a good toxicity against mosquitoes and a low toxicity to mammals[20] and (iii) they target nicotinic acetylcholine receptors which constitute a novel target for malaria v ectors[21,22]
Summary
The introduction of neonicotinoids for managing insecticide resistance in mosquitoes is of high interest as they interact with a biochemical target not previously used in public health. Among the insecticides which are being proposed for managing pyrethroid resistance, neonicotinoids have aroused a high interest as (i) they have not previously been used for public health, (ii) they show a good toxicity against mosquitoes and a low toxicity to mammals[20] and (iii) they target nicotinic acetylcholine receptors (nAChR) which constitute a novel target for malaria v ectors[21,22] In this situation, a new insecticide formulation combining the neonicotinoid clothianidin and the pyrethroid deltamethrin (8:1 w/w) under brand name Fludora Fusion was developed by Bayer to be an additional tool for insecticide resistance management in African malaria vectors. The outcomes of the present study are discussed in the context of the deployment of neonicotinoids for malaria control and the added value of insecticide combinations for insecticide resistance management
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