Methotrexate is highly potent against pyrimethamine-resistant Plasmodium vivax

Mallika Imwong; Bruce Russell; Rossarin Suwanarusk; Alexis Nzila; Mara L. Leimanis; Kanlaya Sriprawat; Supaporn Kaewpongsri; Aung Pyae Phyo; Georges Snounou; Francois Nosten; Laurent Renia

doi:10.1093/infdis/jiq024

Methotrexate is highly potent against pyrimethamine-resistant Plasmodium vivax

Mallika Imwong, Bruce Russell^*, Rossarin Suwanarusk, Alexis Nzila, Mara L. Leimanis, Kanlaya Sriprawat, Supaporn Kaewpongsri, Aung Pyae Phyo, Georges Snounou, Francois Nosten, Laurent Renia

^*Corresponding author for this work

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

18 Scopus citations

Abstract

Resistance of vivax malaria to treatment with antifolates, such as pyrimethamine (Pyr), is spreading as mutations in the dihydrofolatereductase (dhfr) genes are selected and disseminated. We tested the antitumor drug methotrexate (MTX), a potent competitive inhibitor of dhfr, against 11 Plasmodium vivax isolates ex vivo, 10 of which had multiple dhfr mutations associated with Pyr resistance. Despite high-grade resistance to Pyr (median 50% inhibitory concentration [IC₅₀], 13,345 nM), these parasites were all highly susceptible to MTX (median IC₅₀, 2.6 nM). Given its potency against Pyr-resistant P. vivax, the antimalarial potential of MTX deserves further investigation.

Original language	English
Pages (from-to)	207-210
Number of pages	4
Journal	Journal of Infectious Diseases
Volume	203
Issue number	2
DOIs	https://doi.org/10.1093/infdis/jiq024
State	Published - 15 Jan 2011
Externally published	Yes

Bibliographical note

Funding Information:
We thank all of the patients and staff of SMRU for their contribution to this study. SMRU is sponsored by the Wellcome Trust of Great Britain, as part of the Oxford Tropical Medicine Research Programme of Wellcome Trust–Mahidol University. MI is a Wellcome Trust intermediate fellow (Grant 080867/Z/06/Z) and is supported by the Thailand Research Fund and Commission on Higher Education. AN is supported by a Pfizer-Royal Society Award, United Kingdom; the EU Commission under Framework 6 as part of the AntiMal Integrated Project 018834; and the European and Developing Countries Clinical Trials Partnership. LR and GS are currently part of an official collaboration between the Singapore Immunology Network/Agency for Science Technology and Research and Institut National de la Sante et de la Recherche Medicale. Thanks go to Dr. Thierry Diagana (NITD) for his valuable scientific insight and support of this project.

Funding Information:
This work was supported by the Agency for Science Technology and Research (A*STAR, Singapore), Novartis Institute for Tropical Diseases (Singapore), and the Wellcome Trust (United Kingdom).

ASJC Scopus subject areas

General Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1093/infdis/jiq024

Cite this

@article{2d53464ff4124a1ab9431250a0385870,

title = "Methotrexate is highly potent against pyrimethamine-resistant Plasmodium vivax",

abstract = "Resistance of vivax malaria to treatment with antifolates, such as pyrimethamine (Pyr), is spreading as mutations in the dihydrofolatereductase (dhfr) genes are selected and disseminated. We tested the antitumor drug methotrexate (MTX), a potent competitive inhibitor of dhfr, against 11 Plasmodium vivax isolates ex vivo, 10 of which had multiple dhfr mutations associated with Pyr resistance. Despite high-grade resistance to Pyr (median 50% inhibitory concentration [IC50], 13,345 nM), these parasites were all highly susceptible to MTX (median IC50, 2.6 nM). Given its potency against Pyr-resistant P. vivax, the antimalarial potential of MTX deserves further investigation.",

author = "Mallika Imwong and Bruce Russell and Rossarin Suwanarusk and Alexis Nzila and Leimanis, {Mara L.} and Kanlaya Sriprawat and Supaporn Kaewpongsri and Phyo, {Aung Pyae} and Georges Snounou and Francois Nosten and Laurent Renia",

note = "Funding Information: We thank all of the patients and staff of SMRU for their contribution to this study. SMRU is sponsored by the Wellcome Trust of Great Britain, as part of the Oxford Tropical Medicine Research Programme of Wellcome Trust–Mahidol University. MI is a Wellcome Trust intermediate fellow (Grant 080867/Z/06/Z) and is supported by the Thailand Research Fund and Commission on Higher Education. AN is supported by a Pfizer-Royal Society Award, United Kingdom; the EU Commission under Framework 6 as part of the AntiMal Integrated Project 018834; and the European and Developing Countries Clinical Trials Partnership. LR and GS are currently part of an official collaboration between the Singapore Immunology Network/Agency for Science Technology and Research and Institut National de la Sante et de la Recherche Medicale. Thanks go to Dr. Thierry Diagana (NITD) for his valuable scientific insight and support of this project. Funding Information: This work was supported by the Agency for Science Technology and Research (A*STAR, Singapore), Novartis Institute for Tropical Diseases (Singapore), and the Wellcome Trust (United Kingdom).",

year = "2011",

month = jan,

day = "15",

doi = "10.1093/infdis/jiq024",

language = "English",

volume = "203",

pages = "207--210",

journal = "Journal of Infectious Diseases",

issn = "0022-1899",

publisher = "Oxford University Press",

number = "2",

}

TY - JOUR

T1 - Methotrexate is highly potent against pyrimethamine-resistant Plasmodium vivax

AU - Imwong, Mallika

AU - Russell, Bruce

AU - Suwanarusk, Rossarin

AU - Nzila, Alexis

AU - Leimanis, Mara L.

AU - Sriprawat, Kanlaya

AU - Kaewpongsri, Supaporn

AU - Phyo, Aung Pyae

AU - Snounou, Georges

AU - Nosten, Francois

AU - Renia, Laurent

N1 - Funding Information: We thank all of the patients and staff of SMRU for their contribution to this study. SMRU is sponsored by the Wellcome Trust of Great Britain, as part of the Oxford Tropical Medicine Research Programme of Wellcome Trust–Mahidol University. MI is a Wellcome Trust intermediate fellow (Grant 080867/Z/06/Z) and is supported by the Thailand Research Fund and Commission on Higher Education. AN is supported by a Pfizer-Royal Society Award, United Kingdom; the EU Commission under Framework 6 as part of the AntiMal Integrated Project 018834; and the European and Developing Countries Clinical Trials Partnership. LR and GS are currently part of an official collaboration between the Singapore Immunology Network/Agency for Science Technology and Research and Institut National de la Sante et de la Recherche Medicale. Thanks go to Dr. Thierry Diagana (NITD) for his valuable scientific insight and support of this project. Funding Information: This work was supported by the Agency for Science Technology and Research (A*STAR, Singapore), Novartis Institute for Tropical Diseases (Singapore), and the Wellcome Trust (United Kingdom).

PY - 2011/1/15

Y1 - 2011/1/15

N2 - Resistance of vivax malaria to treatment with antifolates, such as pyrimethamine (Pyr), is spreading as mutations in the dihydrofolatereductase (dhfr) genes are selected and disseminated. We tested the antitumor drug methotrexate (MTX), a potent competitive inhibitor of dhfr, against 11 Plasmodium vivax isolates ex vivo, 10 of which had multiple dhfr mutations associated with Pyr resistance. Despite high-grade resistance to Pyr (median 50% inhibitory concentration [IC50], 13,345 nM), these parasites were all highly susceptible to MTX (median IC50, 2.6 nM). Given its potency against Pyr-resistant P. vivax, the antimalarial potential of MTX deserves further investigation.

AB - Resistance of vivax malaria to treatment with antifolates, such as pyrimethamine (Pyr), is spreading as mutations in the dihydrofolatereductase (dhfr) genes are selected and disseminated. We tested the antitumor drug methotrexate (MTX), a potent competitive inhibitor of dhfr, against 11 Plasmodium vivax isolates ex vivo, 10 of which had multiple dhfr mutations associated with Pyr resistance. Despite high-grade resistance to Pyr (median 50% inhibitory concentration [IC50], 13,345 nM), these parasites were all highly susceptible to MTX (median IC50, 2.6 nM). Given its potency against Pyr-resistant P. vivax, the antimalarial potential of MTX deserves further investigation.

UR - http://www.scopus.com/inward/record.url?scp=79851491750&partnerID=8YFLogxK

U2 - 10.1093/infdis/jiq024

DO - 10.1093/infdis/jiq024

M3 - Article

C2 - 21288820

AN - SCOPUS:79851491750

SN - 0022-1899

VL - 203

SP - 207

EP - 210

JO - Journal of Infectious Diseases

JF - Journal of Infectious Diseases

IS - 2

ER -

Methotrexate is highly potent against pyrimethamine-resistant Plasmodium vivax

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

Access to Document

Fingerprint

Cite this