Developing resistance-breaking insecticides at mosquito muscarinic acetylcholine receptors to reduce malaria transmission

The rationale for the proposed research is based on the global health burden that mosquitoes impose, with a focus on the malarial vector Anopheles gambiae. Two specific aims will be performed to test the central hypothesis. Specific Aim #1 will interrogate the pharmacology of An. gambiae mAChR subtypes using a cholinergic chemical library with defined biological and pharmaceutical activity. Specific Aim #2 will focus on the synthesis of a series of analogs of a lead molecule to probe the function of mosquito muscarinic receptor activity, as well as absorption pathways for its dietary delivery. The proposed research is conceptually innovative as it is a departure from the status quo by i) investigating the muscarinic system as an unexploited mode of action to break insecticide resistance, and ii) leveraging midgut nutrient transporters to facilitate dietary uptake of pro- insecticides. This project will provide significant advances to the fields of mosquito biology, as well as insecticide toxicology and development.

NIH project details

Vector-based Strategies

Aug 2021 — Jul 2024

$274,130

United States