Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum

25 Nov 2014

Akhil B. Vaidya, Joanne M. Morrisey, Zhongsheng Zhang, Sudipta Das, Thomas M. Daly, Thomas D. Otto, Natalie J. Spillman, Matthew Wyvratt, Peter Siegl, Jutta Marfurt, Grennady Wirjanata, Boni F. Sebayang, Ric N. Price, Arnab Chatterjee, Advait Nagle, Marcin Stasiak, Susan A. Charman, Iñigo Angulo-Barturen, Santiago Ferrer, María Belén Jiménez-Díaz, María Santos Martínez, Francisco Javier Gamo, Vicky M. Avery, Andrea Ruecker, Michael Delves, Kiaran Kirk, Matthew Berriman, Sandhya Kortagere, Jeremy Burrows, Erkang Fan & Lawrence W. Bergman

Nature Communications

Doi:10.1038/ncomms6521

Abstract

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.

View the full article on Nature's website.