Synergistic Malaria Parasite Killing by Two Types of Plasmodial Surface Anion Channel Inhibitors

• Published in: PloS one Vol. 11; no. 2; p. e0149214
• Main Authors: Pain, Margaret, Fuller, Alexandra W, Basore, Katherine, Pillai, Ajay D, Solomon, Tsione, Bokhari, Abdullah A B, Desai, Sanjay A
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 11.02.2016; Public Library of Science (PLoS)
• Subjects: Analysis; Animals; Anions; Anions - chemistry; Antimalarials - pharmacology; Biological Transport; Biology and Life Sciences; Cell Membrane Permeability - drug effects; Drugs; Erythrocytes; Erythrocytes - cytology; Erythrocytes - parasitology; Humans; Infectious diseases; Inhibitors; Ion Channels - antagonists & inhibitors; Ion Channels - metabolism; Ions; Killing; Laboratories; Macaca mulatta; Malaria; Malaria - drug therapy; Medical screening; Medicine and Health Sciences; Nutrient concentrations; Nutrients; Osmosis; Parasites; Permeability; Physical Sciences; Plasmodium; Plasmodium falciparum; Plasmodium falciparum - drug effects; Plasmodium falciparum - metabolism; Plasmodium knowlesi - drug effects; Plasmodium knowlesi - metabolism; Protozoan Proteins - chemistry; Research and Analysis Methods; Solutes; Structure-function relationships; Synergism; Vector-borne diseases; United States > US; Maryland
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0149214

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.