# Disrupting the mosquito larval midgut using novel pH responsive compounds

> **NIH NIH R21** · UNIVERSITY OF ARIZONA · 2024 · $219,548

## Abstract

Project Summary
 Mosquito borne pathogens afflict millions of people worldwide and their prevalence is anticipated to
increase as mosquitoes and their pathogens become resistant to currently available drugs and insecticides.
While drugs can be used to treat some mosquito borne pathogens, a majority of transmission control comes
through targeting the mosquito vector itself. While insecticides targeting both adult and larval stages are
available, larvicides have the advantage of targeting a constrained target that is unable to readily evade
treatment. Unfortunately, only a few larvicides are available for use and their modes of action are limited.
Thus, there is a critical need for selective novel larvicides with additional modes of action. We have developed
two novel delivery systems that target the uniquely high pH levels of the larval gut. We hypothesize that
provisioning these compounds to immature mosquitoes will allow us to induce lethal effects in mosquitoes of
medical importance. Through a recursive set of aims whereby compounds are readily synthesized, tested and
evaluated we will test this hypothesis in two important mosquito vectors, the malaria vector Anopheles
stephensi and the arboviral vector Aedes aegypti. In Specific Aim 1 we assess the activity of pH responsive
compounds that are tuned to the unique larval midgut environments of Aedes aegypti and Anopheles
stephensi mosquitoes. An initial set of compounds developed by our lab in the MaMa and PTBD classes will be
provisioned to larvae and their efficacy will be assess through SDS-PAGE, imaging, and proteomic studies. In
Specific Aim 2 we will determine the ability of pH sensitive compounds to negatively impact larval
development and deliver larvicidal compounds specifically to the midgut of immature mosquitoes. Compounds
developed to perturb the larval gut will be evaluated for any deleterious effects that they have on the mosquito.
In depth studies of their metabolism, membrane integrity, and larval and adult fitness will be conducted. By the
end of this study, we will have assessed the activity of two chemically distinct sets of compounds in the midgut
of larval mosquitoes. The long-term goal is to develop flexible and highly mosquito-specific larvicidal
compounds with the capacity to leverage unique modes of action.

## Key facts

- **NIH application ID:** 10907803
- **Project number:** 5R21AI177824-02
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** John C Jewett
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $219,548
- **Award type:** 5
- **Project period:** 2023-08-15 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10907803

## Citation

> US National Institutes of Health, RePORTER application 10907803, Disrupting the mosquito larval midgut using novel pH responsive compounds (5R21AI177824-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10907803. Licensed CC0.

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