# How to starve a parasite: Manipulating CoA biosynthesis to control Plasmodium development in the mosquito

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2024 · $616,676

## Abstract

Project Summary
Malaria parasites require pantothenate (Pan) from both the insect and mammalian hosts to synthesize
coenzyme A (CoA) and acetyl-CoA (AC). Further, mosquito-stage parasites cannot take up preformed CoA
from the insect host, so they are entirely dependent on mosquito Pan availability. Thus, we hypothesize that
reducing Pan stores in the mosquito by increasing Pan kinase (PanK) activity and, in turn, CoA biosynthesis
will limit parasite survival in the mosquito, without impacting the availability of CoA/AC to the mosquito itself.
PanK is the rate-limiting enzyme in the CoA biosynthesis pathway and a logical target for our approach. In this
study we will focus on increasing PanK activity in the mosquito to convert Pan into CoA and starve the malaria
parasite of this essential precursor. To accomplish this we will utilize PanK-targeted small molecules or
pantazines and genetic manipulation of PanK in our study host Anopheles stephensi. We will screen
pantazines from a library of compounds developed by our collaborators at St. Jude Children’s Hospital. In
Aim 1, we will use a Go-No Go strategy for pantazine screening that culminates in testing the capacity of
selected pantazines to reduce P. falciparum and Plasmodium yoelii infections in A. stephensi. Aim 2 will
validate the bioactivity and specificity of candidate pantazines identified in the screen in Aim 1. The specificity
of candidate pantazines to activate PanK will be assessed through RNAi or CRISPR/Cas9 knockdown of
PanK, followed by a characterization of the impact on Pan, CoA, AC and parasite infection success.
Concurrent with Aims 1 and 2, we will generate transgenic A. stephensi with increased PanK activity and
determine the impact on Pan levels and parasite survival in Aim 3. The generation of transgenic mosquitoes
with increased midgut PanK expression will contribute to our assessment of PanK-dependent depletion of Pan
stores on parasite infection as well as other aspects of mosquito biology related to vectorial capacity.
Specifically, we will define the effects of mosquito PanK activation, via both pantazine treatment and molecular
manipulations, on A. stephensi lifespan, stress responses, metabolism and reproduction. These studies will
reveal important new insights into nutrient-driven mosquito-parasite interactions that drive parasite infection
success and they will support future efforts to optimize pantazines and novel transgenic lines as distinct
strategies for mosquito-targeted malaria control.

## Key facts

- **NIH application ID:** 10828872
- **Project number:** 5R01AI170506-02
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Shirley Luckhart
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $616,676
- **Award type:** 5
- **Project period:** 2023-04-14 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10828872

## Citation

> US National Institutes of Health, RePORTER application 10828872, How to starve a parasite: Manipulating CoA biosynthesis to control Plasmodium development in the mosquito (5R01AI170506-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10828872. Licensed CC0.

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