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 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 and Lawrence W. Bergman
Additional contact information
Akhil B. Vaidya: Center for Molecular Parasitology, Drexel University College of Medicine
Joanne M. Morrisey: Center for Molecular Parasitology, Drexel University College of Medicine
Zhongsheng Zhang: University of Washington
Sudipta Das: Center for Molecular Parasitology, Drexel University College of Medicine
Thomas M. Daly: Center for Molecular Parasitology, Drexel University College of Medicine
Thomas D. Otto: Wellcome Trust Sanger Institute
Natalie J. Spillman: Research School of Biology, The Australian National University
Matthew Wyvratt: Medicines for Malaria Venture
Peter Siegl: Medicines for Malaria Venture
Jutta Marfurt: Menzies School of Health Research and Charles Darwin University
Grennady Wirjanata: Menzies School of Health Research and Charles Darwin University
Boni F. Sebayang: Eijkman Institute for Molecular Biology
Ric N. Price: Menzies School of Health Research and Charles Darwin University
Arnab Chatterjee: Genomics Institute of the Novartis Research Foundation
Advait Nagle: Genomics Institute of the Novartis Research Foundation
Marcin Stasiak: University of Washington
Susan A. Charman: Center for Drug Candidate Optimisation, Monash University
Iñigo Angulo-Barturen: GlaxoSmithKline, Malaria Support Group
Santiago Ferrer: GlaxoSmithKline, Malaria Support Group
María Belén Jiménez-Díaz: GlaxoSmithKline, Malaria Support Group
María Santos Martínez: GlaxoSmithKline, Malaria Support Group
Francisco Javier Gamo: GlaxoSmithKline, Malaria Support Group
Vicky M. Avery: Eskitis Institute, Griffith University
Andrea Ruecker: South Kensington Campus, Imperial College
Michael Delves: South Kensington Campus, Imperial College
Kiaran Kirk: Research School of Biology, The Australian National University
Matthew Berriman: Wellcome Trust Sanger Institute
Sandhya Kortagere: Center for Molecular Parasitology, Drexel University College of Medicine
Jeremy Burrows: Medicines for Malaria Venture
Erkang Fan: University of Washington
Lawrence W. Bergman: Center for Molecular Parasitology, Drexel University College of Medicine

Nature Communications, 2014, vol. 5, issue 1, 1-10

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6521

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