ArticleScientific reports2016
Comparative chemical genomics reveal that the spiroindolone antimalarial KAE609 (Cipargamin) is a P-type ATPase inhibitor.
Article in Scientific reports, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 54 citations in OpenAlex.
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- Malaria: past, present, and future.Signal transduction and targeted therapy · 2025Review
- The possibilities and challenges associated with selective targetingTransactions of the Royal Society of South Africa. Royal Society of South Africa · 2025Article
- Fungal Plasma Membrane HJournal of fungi (Basel, Switzerland) · 2024Review
- Genetic complexity alters drug susceptibility of asexual and gametocyte stages ofAntimicrobial agents and chemotherapy · 2024Article
- Comparative chemical genomics inProceedings of the National Academy of Sciences of the United States of America · 2024Article
- AssessmentAntimicrobial agents and chemotherapy · 2022Article
- Novel mutation in hexokinase 2 confers resistance to 2-deoxyglucose by altering protein dynamics.PLoS computational biology · 2022Article
- Adaptive laboratory evolution in S. cerevisiae highlights role of transcription factors in fungal xenobiotic resistance.Communications biology · 2022Article
- Transporter-Mediated Solutes Uptake as Drug Target inFrontiers in pharmacology · 2022Review
- Review of the Current Landscape of the Potential of Nanotechnology for Future Malaria Diagnosis, Treatment, and Vaccination Strategies.Pharmaceutics · 2021Review
- Selecting an anti-malarial clinical candidate from two potent dihydroisoquinolones.Malaria journal · 2021Article
- MutantHuntWGS: A Pipeline for IdentifyingG3 (Bethesda, Md.) · 2020Article
- Predicting Drug Resistance Using Deep Mutational Scanning.Molecules (Basel, Switzerland) · 2020Review
- ANS Interacts with the CaJournal of fluorescence · 2020Article
- Pan-active imidazolopiperazine antimalarials target the Plasmodium falciparum intracellular secretory pathway.Nature communications · 2020Article
- Natural Product Inspired Novel Indole based Chiral Scaffold Kills Human Malaria Parasites via Ionic Imbalance Mediated Cell Death.Scientific reports · 2019Article
- Characterization of the ATP4 ion pump inThe Journal of biological chemistry · 2019Article
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Authors and funding
21 authors at 5 institutions in 1 country.
Funding
Abstract
The spiroindolones, a new class of antimalarial medicines discovered in a cellular screen, are rendered less active by mutations in a parasite P-type ATPase, PfATP4. We show here that S. cerevisiae also acquires mutations in a gene encoding a P-type ATPase (ScPMA1) after exposure to spiroindolones and that these mutations are sufficient for resistance. KAE609 resistance mutations in ScPMA1 do not confer resistance to unrelated antimicrobials, but do confer cross sensitivity to the alkyl-lysophospholipid edelfosine, which is known to displace ScPma1p from the plasma membrane. Using an in vitro cell-free assay, we demonstrate that KAE609 directly inhibits ScPma1p ATPase activity. KAE609 also increases cytoplasmic hydrogen ion concentrations in yeast cells. Computer docking into a ScPma1p homology model identifies a binding mode that supports genetic resistance determinants and in vitro experimental structure-activity relationships in both P. falciparum and S. cerevisiae. This model also suggests a shared binding site with the dihydroisoquinolones antimalarials. Our data support a model in which KAE609 exerts its antimalarial activity by directly interfering with P-type ATPase activity.
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