ArticleAntimicrobial agents and chemotherapy2008
Changes in the plasmodial surface anion channel reduce leupeptin uptake and can confer drug resistance in Plasmodium falciparum-infected erythrocytes.
Article in Antimicrobial agents and chemotherapy, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 47 citations in OpenAlex.
- Fluorescent Marinoquinoline Derivative as Inhibitors ofJournal of medicinal chemistry · 2025Article
- Novel Ion Channel Genes in Malaria Parasites.Genes · 2024Review
- Unique Properties of Nutrient Channels onPathogens (Basel, Switzerland) · 2023Review
- In vitro and in vivo evaluation of kinase and protease inhibitors against Trypanosoma evansi.Veterinary research communications · 2023Article
- Malaria therapeutics: are we close enough?Parasites & vectors · 2023Review
- Optimized Pyridazinone Nutrient Channel Inhibitors Are Potent and Specific Antimalarial Leads.Molecular pharmacology · 2022Article
- Epigenetics of malaria parasite nutrient uptake, but why?Trends in parasitology · 2022Review
- Designing antimalarials that break into cells to lock down parasites.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Promises and Pitfalls of Parasite Patch-clamp.Trends in parasitology · 2021Review
- Article
- A Histone Methyltransferase Inhibitor Can Reverse Epigenetically Acquired Drug Resistance in the Malaria Parasite Plasmodium falciparum.Antimicrobial agents and chemotherapy · 2020Article
- Antimalarial Quinoline Drugs Inhibit β-Hematin and Increase Free Hemin Catalyzing Peroxidative Reactions and Inhibition of Cysteine Proteases.Scientific reports · 2019Article
- Identification of Antimalarial Compounds That Require CLAG3 for Their Uptake byAntimicrobial agents and chemotherapy · 2019Article
- Article
- Microbial inhibitors of cysteine proteases.Medical microbiology and immunology · 2016Review
- Plasmodium falciparum Secretome in Erythrocyte and Beyond.Frontiers in microbiology · 2016Review
- A CLAG3 mutation in an amphipathic transmembrane domain alters malaria parasite nutrient channels and confers leupeptin resistance.Infection and immunity · 2015Article
- How do antimalarial drugs reach their intracellular targets?Frontiers in pharmacology · 2015Review
- The conserved clag multigene family of malaria parasites: essential roles in host-pathogen interaction.Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy · 2015Review
- Why do malaria parasites increase host erythrocyte permeability?Trends in parasitology · 2014Review
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
Cysteine protease inhibitors kill malaria parasites and are being pursued for development as antimalarial agents. Because they have multiple targets within bloodstream-stage parasites, workers have assumed that resistance to these inhibitors would not be acquired easily. In the present study, we used in vitro selection to generate a parasite resistant to growth inhibition by leupeptin, a broad-profile cysteine and serine protease inhibitor. Resistance was not associated with upregulation of cysteine protease activity, reduced leupeptin sensitivity of this activity, or expression level changes for putative cysteine or serine proteases in the parasite genome. Instead, it was associated with marked changes in the plasmodial surface anion channel (PSAC), an ion channel on infected erythrocytes that functions in nutrient and bulky organic solute uptake. Osmotic fragility measurements, electrophysiological recordings, and leupeptin uptake studies revealed selective reductions in organic solute permeability via PSAC, altered single-channel gating, and reduced inhibitor affinity. These changes yielded significantly reduced leupeptin uptake and could fully account for the acquired resistance. PSAC represents a novel route for the uptake of bulky hydrophilic compounds acting against intraerythrocytic parasite targets. Drug development based on such compounds should proceed cautiously in light of possible resistance development though the selection of PSAC mutants.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.