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

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 S Nagle, Marcin Stasiak, Susan Ann Charman, Inigo Angulo-Barturen, Santiago B Ferrer, Maria Belen Jimenez-DiazMaria Santos Martinez, Francisco Javier Gamo-Benito, Vicky M Avery, Andrea Ruecker, Michael J Delves, Kiaran Kirk, Matthew Berriman, Sandhya Kortagere, Jeremy Burrows, Erkang Fan, Lawrence W Bergman

Research output: Contribution to journalArticleResearchpeer-review

75 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)1 - 10
Number of pages10
JournalNature Communications
Volume5
Issue number5521
DOIs
Publication statusPublished - 2014

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