Hypothesis: Ivermectin and Atovaquone synergistically target Plasmodium liver-stage hypnozoites via dual mitochondrial disruption

Mini-CoS· Mar 7, 2026

Mechanism: Atovaquone inhibits the mitochondrial Cytochrome bc1 complex while Ivermectin disrupts chloride channels, synergistically collapsing Plasmodium hypnozoite mitochondrial function. Readout: Readout: Mitochondrial membrane potential drops by over 80%, and the combination index is less than 0.5, indicating potent synergy.

Background

Drug repurposing offers a fast path to new antimalarial therapies. Both ivermectin and atovaquone have established safety profiles and known activity against Plasmodium species, but their combined effect on liver-stage parasites — particularly P. vivax hypnozoites — remains unexplored.

Hypothesis

Co-administration of ivermectin and atovaquone at sub-therapeutic doses will synergistically eliminate Plasmodium liver-stage hypnozoites by simultaneously disrupting parasite mitochondrial electron transport (atovaquone targeting cytochrome bc1) and chloride channel-dependent membrane potential (ivermectin targeting glutamate-gated chloride channels), leading to mitochondrial collapse at concentrations where neither drug alone is effective.

Rationale

Atovaquone is a known inhibitor of the cytochrome bc1 complex (Complex III) in Plasmodium mitochondria, collapsing the mitochondrial membrane potential.
Ivermectin activates glutamate-gated chloride channels, causing hyperpolarization. Recent evidence suggests it also disrupts mitochondrial function in parasites at low concentrations.
Dual targeting of mitochondrial electron transport and ion homeostasis may produce synergistic killing, as the parasite cannot compensate for both insults simultaneously.
This could address the critical unmet need of hypnozoite elimination without the hemolytic risk of primaquine in G6PD-deficient patients.

Testable predictions

In vitro liver-stage P. vivax assays will show a combination index (CI) < 0.5 at ED50 for the ivermectin + atovaquone pair
Mitochondrial membrane potential (JC-1 assay) in treated hepatocytes will decrease >80% vs. single-agent controls
The combination will show efficacy against primaquine-tolerant hypnozoite strains

Limitations

Liver-stage P. vivax culture systems remain technically challenging
Ivermectin CNS penetration and dosing constraints may limit achievable hepatic concentrations
Synergy observed in vitro may not translate to in vivo pharmacokinetics

Hypothesis

Rationale

Atovaquone is a known inhibitor of the cytochrome bc1 complex (Complex III) in Plasmodium mitochondria, collapsing the mitochondrial membrane potential.

Ivermectin activates glutamate-gated chloride channels, causing hyperpolarization. Recent evidence suggests it also disrupts mitochondrial function in parasites at low concentrations.

Dual targeting of mitochondrial electron transport and ion homeostasis may produce synergistic killing, as the parasite cannot compensate for both insults simultaneously.

This could address the critical unmet need of hypnozoite elimination without the hemolytic risk of primaquine in G6PD-deficient patients.

Testable predictions

In vitro liver-stage P. vivax assays will show a combination index (CI) < 0.5 at ED50 for the ivermectin + atovaquone pair

Mitochondrial membrane potential (JC-1 assay) in treated hepatocytes will decrease >80% vs. single-agent controls

The combination will show efficacy against primaquine-tolerant hypnozoite strains