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; Lawrence W. Bergman

doi:10.1038/ncomms6521

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-DíazMaría Santos Martínez, Francisco Javier Gamo, Vicky M. Avery, Andrea Ruecker, Michael Delves, Kiaran Kirk, Matthew Berriman, Sandhya Kortagere, Jeremy Burrows, Erkang Fan, Lawrence W. Bergman

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

102 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 language	English
Article number	5521
Journal	Nature Communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms6521
Publication status	Published - 2014

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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., ... Bergman, L. W. (2014). Pyrazoleamide compounds are potent antimalarials that target Na⁺ homeostasis in intraerythrocytic Plasmodium falciparum. Nature Communications, 5, Article 5521. https://doi.org/10.1038/ncomms6521

@article{b833a37394944b98b07f07716851a500,

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.",

author = "Vaidya, {Akhil B.} and Morrisey, {Joanne M.} and Zhongsheng Zhang and Sudipta Das and Daly, {Thomas M.} and Otto, {Thomas D.} and Spillman, {Natalie J.} and Matthew Wyvratt and Peter Siegl and Jutta Marfurt and Grennady Wirjanata and Sebayang, {Boni F.} and Price, {Ric N.} and Arnab Chatterjee and Advait Nagle and Marcin Stasiak and Charman, {Susan A.} and I{\~n}igo Angulo-Barturen and Santiago Ferrer and {Bel{\'e}n Jim{\'e}nez-D{\'i}az}, Mar{\'i}a and Mart{\'i}nez, {Mar{\'i}a Santos} and Gamo, {Francisco Javier} and Avery, {Vicky M.} and Andrea Ruecker and Michael Delves and Kiaran Kirk and Matthew Berriman and Sandhya Kortagere and Jeremy Burrows and Erkang Fan and Bergman, {Lawrence W.}",

year = "2014",

doi = "10.1038/ncomms6521",

language = "English",

volume = "5",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

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Vaidya, AB, Morrisey, JM, Zhang, Z, Das, S, Daly, TM, Otto, TD, Spillman, NJ, Wyvratt, M, Siegl, P, Marfurt, J, Wirjanata, G, Sebayang, BF, Price, RN, Chatterjee, A, Nagle, A, Stasiak, M, Charman, SA, Angulo-Barturen, I, Ferrer, S, Belén Jiménez-Díaz, M, Martínez, MS, Gamo, FJ, Avery, VM, Ruecker, A, Delves, M, Kirk, K, Berriman, M, Kortagere, S, Burrows, J, Fan, E & Bergman, LW 2014, 'Pyrazoleamide compounds are potent antimalarials that target Na⁺ homeostasis in intraerythrocytic Plasmodium falciparum', Nature Communications, vol. 5, 5521. https://doi.org/10.1038/ncomms6521

TY - JOUR

T1 - Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum

AU - Vaidya, Akhil B.

AU - Morrisey, Joanne M.

AU - Zhang, Zhongsheng

AU - Das, Sudipta

AU - Daly, Thomas M.

AU - Otto, Thomas D.

AU - Spillman, Natalie J.

AU - Wyvratt, Matthew

AU - Siegl, Peter

AU - Marfurt, Jutta

AU - Wirjanata, Grennady

AU - Sebayang, Boni F.

AU - Price, Ric N.

AU - Chatterjee, Arnab

AU - Nagle, Advait

AU - Stasiak, Marcin

AU - Charman, Susan A.

AU - Angulo-Barturen, Iñigo

AU - Ferrer, Santiago

AU - Belén Jiménez-Díaz, María

AU - Martínez, María Santos

AU - Gamo, Francisco Javier

AU - Avery, Vicky M.

AU - Ruecker, Andrea

AU - Delves, Michael

AU - Kirk, Kiaran

AU - Berriman, Matthew

AU - Kortagere, Sandhya

AU - Burrows, Jeremy

AU - Fan, Erkang

AU - Bergman, Lawrence W.

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84923311088&partnerID=8YFLogxK

U2 - 10.1038/ncomms6521

DO - 10.1038/ncomms6521

M3 - Article

SN - 2041-1723

VL - 5

JO - Nature Communications

JF - Nature Communications

M1 - 5521

ER -

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

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