Diverse chemotypes disrupt ion homeostasis in the malaria parasite

Summary The antimalarial spiroindolones disrupt P lasmodium falciparum   Na + regulation and induce an alkalinization of the parasite cytosol. It has been proposed that they do so by inhibiting PfATP 4, a parasite plasma membrane P ‐type ATP ase postulated to export Na + and import H + equivalents. Here, we screened the 400 antiplasmodial compounds of the open access ‘ M alaria B ox’ for their effects on parasite ion regulation. Twenty eight compounds affected parasite Na + and pH regulation in a manner consistent with PfATP 4 inhibition. Six of these, with chemically diverse structures, were selected for further analysis. All six showed reduced antiplasmodial activity against spiroindolone‐resistant parasites carrying mutations in pfatp4 . We exposed parasites to incrementally increasing concentrations of two of the six compounds and in both cases obtained resistant parasites with mutations in pfatp4 . The finding that diverse chemotypes have an apparently similar mechanism of action indicates that PfATP 4 may be a significant Achilles' heel for the parasite.