# Dual artemisinin action combats resistance

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2022 · $569,412

## Abstract

Summary
 The broad long-term goal is to optimize critical artemisinin and quinoline malaria drug combinations for maximum
killing of the P. falciparum parasite by defeating resistance. In the setting of ongoing drug resistance to currently
deployed drugs, this work will quantify a novel quinoline-like mechanism of action for the heme-artemisinin adducts,
define reversible or irreversible heme crystal inhibition correlated to level of drug resistance, and explore optimum
heme crystal inhibition related to parasite killing with quinoline-artemisinin combinations. Preliminary data validate
an additional mechanism of action for the artemisinins based on formation of abundant heme-artemisinin adduct,
which inhibits heme crystallization with irreversible action. Exogenous heme-artemisinin adducts inhibit artemisinin
ring-resistant mutant Kelch13 P. falciparum parasites with low nM IC50s. The experimental approach employs the
synergy between experimental investigations with P. falciparum drug-sensitive and resistant parasites in vitro and
physicochemical insights obtained by time-resolved in situ observations of crystal growth by atomic force microscopy
in the presence of different drug combinations.
 The hypothesis is that the inhibition of heme crystal formation by the heme adduct of dihydroartemisinin (DHA,
the product of most artemisinin-class drugs in vivo) renders trophozoites of any Plasmodium isolate sensitive, which
defeats the artemisinin ring-stage resistance. We also hypothesize that certain combinations of quinolines and
heme-dihydroartemisinin adduct (H-DHA) are superior in killing of parasites correlated to heme crystal inhibition as
well as separately to the degree of reversible/irreversible heme crystal inhibition. Towards these objectives, we will
pursue three specific aims: Aim 1. Establish the inhibition concentrations and mechanism of action of exogenous as
well as bio-activated H-DHA in drug sensitive and resistant Plasmodium. Aim 2. Establish reversibility or irreversibility
of H-DHA heme crystal inhibition in vivo and in vitro. Aim 3. Establish if double combinations of antimalarial quinolines
and H-DHA adducts enhance, weaken, or are indifferent to their partner’s action on parasite killing and the rate of
hematin crystallization.
 This proposed research will quantify the amount of parasite killing by artemisinin adduct metabolites which
renders trophozoite stages sensitive to the artemisinin drug class. The work will also inform fundamental knowledge
regarding mechanisms to defeat artemisinin resistance, degree of reversibility of hematin crystal growth, and
optimum combinations of malaria drugs based upon interaction effects.

## Key facts

- **NIH application ID:** 10374922
- **Project number:** 5R01AI150763-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** DAVID Joseph SULLIVAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $569,412
- **Award type:** 5
- **Project period:** 2021-03-18 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10374922

## Citation

> US National Institutes of Health, RePORTER application 10374922, Dual artemisinin action combats resistance (5R01AI150763-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10374922. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*