title: Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum.
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.
authors.affiliation: Department of Microbiology and Immunology, Center for Molecular Parasitology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, Pennsylvania 190129, USA.
authors.forename: Akhil B
authors.initials: AB
authors.lastname: Vaidya
authors.affiliation: Department of Microbiology and Immunology, Center for Molecular Parasitology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, Pennsylvania 190129, USA.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Morrisey
authors.affiliation: Department of Biochemistry, University of Washington, Box 357350, Seattle, Washington 98195, USA.
authors.forename: Zhongsheng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Microbiology and Immunology, Center for Molecular Parasitology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, Pennsylvania 190129, USA.
authors.forename: Sudipta
authors.initials: S
authors.lastname: Das
authors.affiliation: Department of Microbiology and Immunology, Center for Molecular Parasitology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, Pennsylvania 190129, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Daly
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB101SA, UK.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Otto
authors.affiliation: Research School of Biology, The Australian National University, Canberra, Australian Capital Territory 0200, Australia.
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Spillman
authors.affiliation: Medicines for Malaria Venture, PO Box 1826, 20Rt de Pr-Bois, Geneva 15 1215, Switzerland.
authors.forename: Matthew
authors.initials: M
authors.lastname: Wyvratt
authors.affiliation: Medicines for Malaria Venture, PO Box 1826, 20Rt de Pr-Bois, Geneva 15 1215, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Siegl
authors.affiliation: Division of Global and Tropical Health, Menzies School of Health Research and Charles Darwin University, PO Box 41096, Casuarina, Northern Territory 0811, Australia.
authors.forename: Jutta
authors.initials: J
authors.lastname: Marfurt
authors.affiliation: Division of Global and Tropical Health, Menzies School of Health Research and Charles Darwin University, PO Box 41096, Casuarina, Northern Territory 0811, Australia.
authors.forename: Grennady
authors.initials: G
authors.lastname: Wirjanata
authors.affiliation: Eijkman Institute for Molecular Biology, Jl. Diponegoro 69, Jakarta 10430, Indonesia.
authors.forename: Boni F
authors.initials: BF
authors.lastname: Sebayang
authors.affiliation: 1] Division of Global and Tropical Health, Menzies School of Health Research and Charles Darwin University, PO Box 41096, Casuarina, Northern Territory 0811, Australia [2] Nuffield Department of Clinical Medicine, Centre for Tropical Medicine, University of Oxford, Oxford OX3 7LJ, UK.
authors.forename: Ric N
authors.initials: RN
authors.lastname: Price
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
authors.forename: Arnab
authors.initials: A
authors.lastname: Chatterjee
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
authors.forename: Advait
authors.initials: A
authors.lastname: Nagle
authors.affiliation: Department of Biochemistry, University of Washington, Box 357350, Seattle, Washington 98195, USA.
authors.forename: Marcin
authors.initials: M
authors.lastname: Stasiak
authors.affiliation: Center for Drug Candidate Optimisation, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.affiliation: GlaxoSmithKline, Malaria Support Group, Calle Severo Ochoa 2, Tres Cantos 28760, Spain.
authors.forename: Iñigo
authors.initials: I
authors.lastname: Angulo-Barturen
authors.affiliation: GlaxoSmithKline, Malaria Support Group, Calle Severo Ochoa 2, Tres Cantos 28760, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Ferrer
authors.affiliation: GlaxoSmithKline, Malaria Support Group, Calle Severo Ochoa 2, Tres Cantos 28760, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Belén Jiménez-Díaz
authors.affiliation: GlaxoSmithKline, Malaria Support Group, Calle Severo Ochoa 2, Tres Cantos 28760, Spain.
authors.forename: María Santos
authors.initials: MS
authors.lastname: Martínez
authors.affiliation: GlaxoSmithKline, Malaria Support Group, Calle Severo Ochoa 2, Tres Cantos 28760, Spain.
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Gamo
authors.affiliation: Eskitis Institute, Griffith University, Don Young Road, Nathan, Queensland 4111, Australia.
authors.forename: Vicky M
authors.initials: VM
authors.lastname: Avery
authors.affiliation: Department of Life Sciences, South Kensington Campus, Imperial College, London SW7 2AZ, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ruecker
authors.affiliation: Department of Life Sciences, South Kensington Campus, Imperial College, London SW7 2AZ, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Delves
authors.affiliation: Research School of Biology, The Australian National University, Canberra, Australian Capital Territory 0200, Australia.
authors.forename: Kiaran
authors.initials: K
authors.lastname: Kirk
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB101SA, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Berriman
authors.affiliation: Department of Microbiology and Immunology, Center for Molecular Parasitology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, Pennsylvania 190129, USA.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Kortagere
authors.affiliation: Medicines for Malaria Venture, PO Box 1826, 20Rt de Pr-Bois, Geneva 15 1215, Switzerland.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Burrows
authors.affiliation: Department of Biochemistry, University of Washington, Box 357350, Seattle, Washington 98195, USA.
authors.forename: Erkang
authors.initials: E
authors.lastname: Fan
authors.affiliation: Department of Microbiology and Immunology, Center for Molecular Parasitology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, Pennsylvania 190129, USA.
authors.forename: Lawrence W
authors.initials: LW
authors.lastname: Bergman
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000577:Amides / Q000494:pharmacology*; D000962:Antimalarials / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D004912:Erythrocytes / Q000469:parasitology*; D005260:Female; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D008288:Malaria / Q000469:parasitology*; D008297:Male; D010962:Plasmodium berghei / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D015800:Protozoan Proteins; D011720:Pyrazoles / Q000494:pharmacology*; D012964:Sodium / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases
chemical_list: D000251:Adenosine Triphosphatases; D000577:Amides; D000962:Antimalarials; D001562:Benzimidazoles; D011494:Protein Kinases; D015800:Protozoan Proteins; D011720:Pyrazoles; D012964:Sodium; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C000622264:PA21A050; C031280:pyrazole