Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum.
Vaidya AB., Morrisey JM., Zhang Z., Das S., Daly TM., Otto TD., Spillman NJ., Wyvratt M., Siegl P., Marfurt J., Wirjanata G., Sebayang BF., Price RN., Chatterjee A., Nagle A., Stasiak M., Charman SA., Angulo-Barturen I., Ferrer S., Belén Jiménez-Díaz M., Martínez MS., Gamo FJ., Avery VM., Ruecker A., Delves M., Kirk K., Berriman M., Kortagere S., Burrows J., Fan E., Bergman LW.
The quest for new antimalarial drugs, especially those with novel modes of action, is essential in the face of emerging drug-resistant parasites. Here we describe a new chemical class of molecules, pyrazoleamides, with potent activity against human malaria parasites and showing remarkably rapid parasite clearance in an in vivo model. Investigations involving pyrazoleamide-resistant parasites, whole-genome sequencing and gene transfers reveal that mutations in two proteins, a calcium-dependent protein kinase (PfCDPK5) and a P-type cation-ATPase (PfATP4), are necessary to impart full resistance to these compounds. A pyrazoleamide compound causes a rapid disruption of Na(+) regulation in blood-stage Plasmodium falciparum parasites. Similar effect on Na(+) homeostasis was recently reported for spiroindolones, which are antimalarials of a chemical class quite distinct from pyrazoleamides. Our results reveal that disruption of Na(+) homeostasis in malaria parasites is a promising mode of antimalarial action mediated by at least two distinct chemical classes.