A drug-selected Plasmodium falciparum lacking the need for conventional electron transport

Martin J. Smilkstein; Isaac Forquer; Atsuko Kanazawa; Jane Xu Kelly; Rolf W. Winter; David J. Hinrichs; David M. Kramer; Michael K. Riscoe

doi:10.1016/j.molbiopara.2008.01.002

A drug-selected Plasmodium falciparum lacking the need for conventional electron transport

Martin J. Smilkstein, Isaac Forquer, Atsuko Kanazawa, Jane Xu Kelly, Rolf W. Winter, David J. Hinrichs, David M. Kramer, Michael K. Riscoe

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

25 Scopus citations

Abstract

Mitochondrial electron transport is essential for survival in Plasmodium falciparum, making the cytochrome (cyt) bc₁ complex an attractive target for antimalarial drug development. Here we report that P. falciparum cultivated in the presence of a novel cyt bc₁ inhibitor underwent a fundamental transformation in biochemistry to a phenotype lacking a requirement for electron transport through the cyt bc₁ complex. Growth of the drug-selected parasite clone (SB1-A6) is robust in the presence of diverse cyt bc₁ inhibitors, although electron transport is fully inhibited by these same agents. This transformation defies expected molecular-based concepts of drug resistance, has important implications for the study of cyt bc₁ as an antimalarial drug target, and may offer a glimpse into the evolutionary future of Plasmodium.

Original language	English (US)
Pages (from-to)	64-68
Number of pages	5
Journal	Molecular and Biochemical Parasitology
Volume	159
Issue number	1
DOIs	https://doi.org/10.1016/j.molbiopara.2008.01.002
State	Published - May 2008
Externally published	Yes

Keywords

Complex III
Drug resistance
Electron transport
Malaria
Plasmodium

ASJC Scopus subject areas

Parasitology
Molecular Biology

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10.1016/j.molbiopara.2008.01.002

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title = "A drug-selected Plasmodium falciparum lacking the need for conventional electron transport",

abstract = "Mitochondrial electron transport is essential for survival in Plasmodium falciparum, making the cytochrome (cyt) bc1 complex an attractive target for antimalarial drug development. Here we report that P. falciparum cultivated in the presence of a novel cyt bc1 inhibitor underwent a fundamental transformation in biochemistry to a phenotype lacking a requirement for electron transport through the cyt bc1 complex. Growth of the drug-selected parasite clone (SB1-A6) is robust in the presence of diverse cyt bc1 inhibitors, although electron transport is fully inhibited by these same agents. This transformation defies expected molecular-based concepts of drug resistance, has important implications for the study of cyt bc1 as an antimalarial drug target, and may offer a glimpse into the evolutionary future of Plasmodium.",

keywords = "Complex III, Drug resistance, Electron transport, Malaria, Plasmodium",

author = "Smilkstein, {Martin J.} and Isaac Forquer and Atsuko Kanazawa and Kelly, {Jane Xu} and Winter, {Rolf W.} and Hinrichs, {David J.} and Kramer, {David M.} and Riscoe, {Michael K.}",

note = "Funding Information: WR243251 and P. falciparum TM90C2B were provided by Wil Milhous and Dennis Kyle, respectively. OptiMAL {\textregistered} test strips and reagents were a gift from Michael Makler. Akhil Vaidya generously contributed his insight during discussions prior to and during manuscript preparation. Erin Riscoe assisted with in vitro drug susceptibility growth assays. Funds to support this project were received from the U.S. Department of Veterans Affairs (Portland working group) and the U.S. National Institutes of Health, Grant 2 R01 GM061904 (Pullman working group). ",

year = "2008",

month = may,

doi = "10.1016/j.molbiopara.2008.01.002",

language = "English (US)",

volume = "159",

pages = "64--68",

journal = "Molecular and Biochemical Parasitology",

issn = "0166-6851",

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AU - Smilkstein, Martin J.

AU - Forquer, Isaac

AU - Kanazawa, Atsuko

AU - Kelly, Jane Xu

AU - Winter, Rolf W.

AU - Hinrichs, David J.

AU - Kramer, David M.

AU - Riscoe, Michael K.

N1 - Funding Information: WR243251 and P. falciparum TM90C2B were provided by Wil Milhous and Dennis Kyle, respectively. OptiMAL ® test strips and reagents were a gift from Michael Makler. Akhil Vaidya generously contributed his insight during discussions prior to and during manuscript preparation. Erin Riscoe assisted with in vitro drug susceptibility growth assays. Funds to support this project were received from the U.S. Department of Veterans Affairs (Portland working group) and the U.S. National Institutes of Health, Grant 2 R01 GM061904 (Pullman working group).

PY - 2008/5

Y1 - 2008/5

N2 - Mitochondrial electron transport is essential for survival in Plasmodium falciparum, making the cytochrome (cyt) bc1 complex an attractive target for antimalarial drug development. Here we report that P. falciparum cultivated in the presence of a novel cyt bc1 inhibitor underwent a fundamental transformation in biochemistry to a phenotype lacking a requirement for electron transport through the cyt bc1 complex. Growth of the drug-selected parasite clone (SB1-A6) is robust in the presence of diverse cyt bc1 inhibitors, although electron transport is fully inhibited by these same agents. This transformation defies expected molecular-based concepts of drug resistance, has important implications for the study of cyt bc1 as an antimalarial drug target, and may offer a glimpse into the evolutionary future of Plasmodium.

AB - Mitochondrial electron transport is essential for survival in Plasmodium falciparum, making the cytochrome (cyt) bc1 complex an attractive target for antimalarial drug development. Here we report that P. falciparum cultivated in the presence of a novel cyt bc1 inhibitor underwent a fundamental transformation in biochemistry to a phenotype lacking a requirement for electron transport through the cyt bc1 complex. Growth of the drug-selected parasite clone (SB1-A6) is robust in the presence of diverse cyt bc1 inhibitors, although electron transport is fully inhibited by these same agents. This transformation defies expected molecular-based concepts of drug resistance, has important implications for the study of cyt bc1 as an antimalarial drug target, and may offer a glimpse into the evolutionary future of Plasmodium.

KW - Complex III

KW - Drug resistance

KW - Electron transport

KW - Malaria

KW - Plasmodium

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A drug-selected Plasmodium falciparum lacking the need for conventional electron transport

Abstract

Keywords

ASJC Scopus subject areas

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