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 S Nagle, Marcin Stasiak, Susan Ann Charman, Inigo Angulo-Barturen, Santiago B Ferrer, Maria Belen Jimenez-Diaz & 11 others Maria Santos Martinez, Francisco Javier Gamo-Benito, Vicky M Avery, Andrea Ruecker, Michael J Delves, Kiaran Kirk, Matthew Berriman, Sandhya Kortagere, Jeremy Burrows, Erkang Fan, Lawrence W Bergman

Research output: Contribution to journalArticleResearchpeer-review

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 languageEnglish
Pages (from-to)1 - 10
Number of pages10
JournalNature Communications
Volume5
Issue number5521
DOIs
Publication statusPublished - 2014

Cite this

Vaidya, A. B., Morrisey, J. M., Zhang, Z., Das, S., Daly, T. M., Otto, T. D., ... Bergman, L. W. (2014). Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum. Nature Communications, 5(5521), 1 - 10. https://doi.org/10.1038/ncomms6521
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 S ; Stasiak, Marcin ; Charman, Susan Ann ; Angulo-Barturen, Inigo ; Ferrer, Santiago B ; Jimenez-Diaz, Maria Belen ; Martinez, Maria Santos ; Gamo-Benito, Francisco Javier ; Avery, Vicky M ; Ruecker, Andrea ; Delves, Michael J ; Kirk, Kiaran ; Berriman, Matthew ; Kortagere, Sandhya ; Burrows, Jeremy ; Fan, Erkang ; Bergman, Lawrence W. / Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum. In: Nature Communications. 2014 ; Vol. 5, No. 5521. pp. 1 - 10.
@article{e42b43ad115b4dcc89ced83dfbdada1d,
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 Nagle, {Advait S} and Marcin Stasiak and Charman, {Susan Ann} and Inigo Angulo-Barturen and Ferrer, {Santiago B} and Jimenez-Diaz, {Maria Belen} and Martinez, {Maria Santos} and Gamo-Benito, {Francisco Javier} and Avery, {Vicky M} and Andrea Ruecker and Delves, {Michael J} 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",
pages = "1 -- 10",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "5521",

}

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, AS, Stasiak, M, Charman, SA, Angulo-Barturen, I, Ferrer, SB, Jimenez-Diaz, MB, Martinez, MS, Gamo-Benito, FJ, Avery, VM, Ruecker, A, Delves, MJ, 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, no. 5521, pp. 1 - 10. https://doi.org/10.1038/ncomms6521

Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum. / 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 S; Stasiak, Marcin; Charman, Susan Ann; Angulo-Barturen, Inigo; Ferrer, Santiago B; Jimenez-Diaz, Maria Belen; Martinez, Maria Santos; Gamo-Benito, Francisco Javier; Avery, Vicky M; Ruecker, Andrea; Delves, Michael J; Kirk, Kiaran; Berriman, Matthew; Kortagere, Sandhya; Burrows, Jeremy; Fan, Erkang; Bergman, Lawrence W.

In: Nature Communications, Vol. 5, No. 5521, 2014, p. 1 - 10.

Research output: Contribution to journalArticleResearchpeer-review

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 S

AU - Stasiak, Marcin

AU - Charman, Susan Ann

AU - Angulo-Barturen, Inigo

AU - Ferrer, Santiago B

AU - Jimenez-Diaz, Maria Belen

AU - Martinez, Maria Santos

AU - Gamo-Benito, Francisco Javier

AU - Avery, Vicky M

AU - Ruecker, Andrea

AU - Delves, Michael J

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.nature.com/ncomms/2014/141125/ncomms6521/pdf/ncomms6521.pdf

U2 - 10.1038/ncomms6521

DO - 10.1038/ncomms6521

M3 - Article

VL - 5

SP - 1

EP - 10

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 5521

ER -