Cation ATPase (ATP4) Orthologue Replacement in the Malaria Parasite Plasmodium knowlesi Reveals Species-Specific Responses to ATP4-Targeting Drugs
Franziska Mohring, Donelly A. van Schalkwyk, Ryan C. Henrici, Benjamin Blasco, Didier Leroy, Colin J. Sutherland, Robert W. Moon
Abstract
Effective drugs are vital to minimize the illness and death caused by malaria. Development of new drugs becomes ever more urgent as drug resistance emerges. Among promising compounds now being developed to treat malaria are several unrelated molecules that each inhibit the same protein in the malaria parasite-ATP4. Here, we exploited the genetic tractability of P. knowlesi to replace its own ATP4 genes with orthologues from five human-infective species to understand the drug susceptibility differences among these parasites. We previously estimated the susceptibility to ATP4-targeting drugs of each species using clinical samples from malaria patients. These estimates closely matched those of the corresponding "hybrid" P. knowlesi parasites carrying introduced ATP4 genes. Thus, species-specific ATP4 inhibitor efficacy is directly determined by the sequence of the gene. Our novel approach to understanding cross-species susceptibility/resistance can strongly support the effort to develop antimalarials that effectively target all human malaria parasite species.