title: Synergistic Malaria Parasite Killing by Two Types of Plasmodial Surface Anion Channel Inhibitors.
abstract: Malaria parasites increase their host erythrocyte's permeability to a broad range of ions and organic solutes. The plasmodial surface anion channel (PSAC) mediates this uptake and is an established drug target. Development of therapies targeting this channel is limited by several problems including interactions between known inhibitors and permeating solutes that lead to incomplete channel block. Here, we designed and executed a high-throughput screen to identify a novel class of PSAC inhibitors that overcome this solute-inhibitor interaction. These new inhibitors differ from existing blockers and have distinct effects on channel-mediated transport, supporting a model of two separate routes for solute permeation though PSAC. Combinations of inhibitors specific for the two routes had strong synergistic action against in vitro parasite propagation, whereas combinations acting on a single route produced only additive effects. The magnitude of synergism depended on external nutrient concentrations, consistent with an essential role of the channel in parasite nutrient acquisition. The identified inhibitors will enable a better understanding of the channel's structure-function and may be starting points for novel combination therapies that produce synergistic parasite killing.
authors: The Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America.
authors: Margaret
authors: M
authors: Pain
authors: The Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America.
authors: Alexandra W
authors: AW
authors: Fuller
authors: The Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America.
authors: Katherine
authors: K
authors: Basore
authors: The Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America.
authors: Ajay D
authors: AD
authors: Pillai
authors: The Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America.
authors: Tsione
authors: T
authors: Solomon
authors: The Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America.
authors: Abdullah A B
authors: AA
authors: Bokhari
authors: The Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America.
authors: Sanjay A
authors: SA
authors: Desai
mesh_terms: D000818:Animals; D000838:Anions / Q000737:chemistry; D000962:Antimalarials / Q000494:pharmacology*; D001692:Biological Transport; D002463:Cell Membrane Permeability / Q000187:drug effects; D004912:Erythrocytes / Q000166:cytology / Q000469:parasitology; D006801:Humans; D007473:Ion Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007477:Ions; D008253:Macaca mulatta; D008288:Malaria / Q000188:drug therapy*; D009995:Osmosis; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000378:metabolism; D016790:Plasmodium knowlesi / Q000187:drug effects* / Q000378:metabolism; D015800:Protozoan Proteins / Q000737:chemistry
chemical_list: D000838:Anions; D000962:Antimalarials; D007473:Ion Channels; D007477:Ions; D015800:Protozoan Proteins