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

authors

  • Vaidya, Akhil B.
  • Morrisey, Joanne M.
  • Zhang, Zhongsheng
  • Das, Sudipta
  • Daly, Thomas M.
  • Otto, Thomas D.
  • Spillman, Natalie J.
  • Wyvratt, Matthew
  • Siegl, Peter
  • Marfurt, Jutta
  • Wirjanata, Grennady
  • Sebayang, Boni F.
  • Price, Ric N.
  • Chatterjee, Arnab
  • Nagle, Advait
  • Stasiak, Marcin
  • Charman, Susan A.
  • Angulo Barturen, Iñigo
  • FERRER BAZAGA, SANTIAGO
  • Belen Jimenez Diaz, Maria
  • Martinez, Maria Santos
  • Gamo, Francisco Javier
  • Avery, Vicky M.
  • Ruecker, Andrea
  • Delves, Michael
  • Kirk, Kiaran
  • Berriman, Matthew
  • Kortagere, Sandhya
  • Burrows, Jeremy
  • Fan, Erkang
  • Bergman, Lawrence W.

publication date

  • January 2014

start page

  • 1

end page

  • 10

issue

  • 5521

volume

  • 5

Electronic International Standard Serial Number (EISSN)

  • 2041-1723

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.

subjects

  • Biology and Biomedicine
  • Medicine