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

Vaidya, A. B. et al. (2014) Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum. Nature Communications, 5, 5521. (doi: 10.1038/ncomms6521) (PMID:25422853) (PMCID:PMC4263321)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Otto, Professor Thomas
• Authors: Vaidya, A. B., Morrisey, J. M., Zhang, Z., Das, S., Daly, T. M., Otto, T. D., Spillman, N. j., Wyvratt, M., Siegl, P., Marfurt, J., Wirjanata, G., Sebayang, B. F., Price, R. N., Chatterjee, A., Nagle, A., Stasiak, M., Charman, S. A., Angulo-Barturen, I., Ferrer, S., Belén Jiménez-Díaz, M., Martínez, M. S., Gamo, F. J., Avery, V. M., Ruecker, A., Delves, M., Kirk, K., Berriman, M., Kortagere, S., Burrows, J., Fan, E., and Bergman, L. W.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Nature Communications
• Publisher: Nature Publishing Group
• ISSN: 2041-1723
• Published Online: 25 November 2014
• Copyright Holders: Copyright © 2014 Macmillan Publishers Limited
• First Published: First published in Nature Communications 5:5521
• Publisher Policy: Reproduced under a Creative Commons License