Preemptive discovery of insecticide cross-resistance mechanisms for next generation malaria control products

Malaria control is being impacted by insecticide resistance but newly-available and oncoming insecticides offer the opportunity to effectively manage resistance, provided mechanistic knowledge and monitoring tools become available to inform rational deployment. Genomic and transcriptomic comparisons of resistant and susceptible mosquitoes, which we and others are applying as part of ongoing and recent programmes are powerful for identification of resistance candidates, but lack capacity to pre-emptively identify mechanisms of resistance and cross-resistance for new insecticides. Novel complementary approaches are required to meet this challenge and we propose to combine transcriptomic and functional genomic approaches with a novel chemico-proteomic approach, Activity Based Protein Profiling (ABPP ). We will apply dual pipelines: the first integrates comparative transcriptomic and ABPP analyses to identify differentially expressed genes and correspondent differentially binding enzymes between Anopheles strains with contrasting resistance to the key current IRS insecticide pirimiphos methyl (PM). The second pipeline will apply competitive inhibition of ABPs with insecticide or their reactive metabolites to identify modes of toxicity for each and generate an insecticide-enzyme interaction matrix for identification of cross-resistance candidates. The most promising candidates from each pipeline will be tested using a third functional validation pipeline involving heterologous expression and metabolism, transgenic expression in Drosophila and Anopheles and RNAi to investigate resultant gains and loss of resistance. Our results will provide new knowledge and pre-emptive diagnostic tools for resistance management programmes, and pipelines readily adaptable to future insecticides

Project details

Insecticide Resistance

Feb 2021 — Jan 2024

$1.06M

United Kingdom