Fungal Metabolite Cryptosporin Shows Antimalarial Promise With Low Resistance Risk
Researchers found that cryptosporin, a natural product from the fungus Acaromyces ingoldii, effectively kills malaria parasites through a novel mechanism involving oxidative stress rather than targeting mitochondria. The parasite develops resistance primarily through a mutation in an aquaglyceroporin gene and duplication of antioxidant genes, suggesting a low overall risk of widespread resistance. This discovery could lead to new antimalarial treatments with a different mechanism than existing drugs like artemisinin.
A preprint study describes cryptosporin's potent activity against both blood-stage and liver-stage malaria parasites with minimal toxicity to human cells. Unlike the drug atovaquone, cryptosporin does not target mitochondrial electron transport, suggesting a distinct mechanism of action. Through in vitro evolution and genomic analysis, researchers identified that parasites develop resistance via a specific mutation (F138Y) in the PfAQP aquaglyceroporin gene and duplications of superoxide dismutase genes, indicating the drug likely works by inducing oxidative stress. CRISPR/Cas9 experiments confirmed the aquaglyceroporin mutation is sufficient for resistance. The minimum inoculum of resistance—a measure of how easily resistance emerges—was low, suggesting cryptosporin may have favorable resistance development characteristics compared to some existing antimalarials.
What's missing
The study's own limitations warrant consideration: the resistance mechanism was identified through in vitro evolution under laboratory conditions, which may not fully reflect resistance development in natural parasite populations; clinical efficacy and safety in human patients remain untested; the study does not discuss potential cross-resistance with other antimalarial classes or the drug's pharmacokinetic properties in vivo.
What different sources said
- bioRxivCenter
Duplication of superoxide dismutase and a mutation in aquaglyceroporin mediates the sensitivity of Plasmodium falciparum to cryptosporin, a natural product derived from Acaromyces ingoldii
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