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Na(+) Influx Induced by New Antimalarials Causes Rapid Alterations in the Cholesterol Content and Morphology of Plasmodium falciparum

Among the several new antimalarials discovered over the past decade are at least three clinical candidate drugs, each with a distinct chemical structure, that disrupt Na(+) homeostasis resulting in a rapid increase in intracellular Na+ concentration ([Na(+)](i)) within the erythrocytic stages of Pla...

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Autores principales: Das, Sudipta, Bhatanagar, Suyash, Morrisey, Joanne M., Daly, Thomas M., Burns, James M., Coppens, Isabelle, Vaidya, Akhil B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881962/
https://www.ncbi.nlm.nih.gov/pubmed/27227970
http://dx.doi.org/10.1371/journal.ppat.1005647
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author Das, Sudipta
Bhatanagar, Suyash
Morrisey, Joanne M.
Daly, Thomas M.
Burns, James M.
Coppens, Isabelle
Vaidya, Akhil B.
author_facet Das, Sudipta
Bhatanagar, Suyash
Morrisey, Joanne M.
Daly, Thomas M.
Burns, James M.
Coppens, Isabelle
Vaidya, Akhil B.
author_sort Das, Sudipta
collection PubMed
description Among the several new antimalarials discovered over the past decade are at least three clinical candidate drugs, each with a distinct chemical structure, that disrupt Na(+) homeostasis resulting in a rapid increase in intracellular Na+ concentration ([Na(+)](i)) within the erythrocytic stages of Plasmodium falciparum. At present, events triggered by Na(+) influx that result in parasite demise are not well-understood. Here we report effects of two such drugs, a pyrazoleamide and a spiroindolone, on intraerythrocytic P. falciparum. Within minutes following the exposure to these drugs, the trophozoite stage parasite, which normally contains little cholesterol, was made permeant by cholesterol-dependent detergents, suggesting it acquired a substantial amount of the lipid. Consistently, the merozoite surface protein 1 and 2 (MSP1 and MSP2), glycosylphosphotidylinositol (GPI)-anchored proteins normally uniformly distributed in the parasite plasma membrane, coalesced into clusters. These alterations were not observed following drug treatment of P. falciparum parasites adapted to grow in a low [Na(+)] growth medium. Both cholesterol acquisition and MSP1 coalescence were reversible upon the removal of the drugs, implicating an active process of cholesterol exclusion from trophozoites that we hypothesize is inhibited by high [Na(+)](i). Electron microscopy of drug-treated trophozoites revealed substantial morphological changes normally seen at the later schizont stage including the appearance of partial inner membrane complexes, dense organelles that resemble “rhoptries” and apparent nuclear division. Together these results suggest that [Na(+)](i) disruptor drugs by altering levels of cholesterol in the parasite, dysregulate trophozoite to schizont development and cause parasite demise.
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spelling pubmed-48819622016-06-10 Na(+) Influx Induced by New Antimalarials Causes Rapid Alterations in the Cholesterol Content and Morphology of Plasmodium falciparum Das, Sudipta Bhatanagar, Suyash Morrisey, Joanne M. Daly, Thomas M. Burns, James M. Coppens, Isabelle Vaidya, Akhil B. PLoS Pathog Research Article Among the several new antimalarials discovered over the past decade are at least three clinical candidate drugs, each with a distinct chemical structure, that disrupt Na(+) homeostasis resulting in a rapid increase in intracellular Na+ concentration ([Na(+)](i)) within the erythrocytic stages of Plasmodium falciparum. At present, events triggered by Na(+) influx that result in parasite demise are not well-understood. Here we report effects of two such drugs, a pyrazoleamide and a spiroindolone, on intraerythrocytic P. falciparum. Within minutes following the exposure to these drugs, the trophozoite stage parasite, which normally contains little cholesterol, was made permeant by cholesterol-dependent detergents, suggesting it acquired a substantial amount of the lipid. Consistently, the merozoite surface protein 1 and 2 (MSP1 and MSP2), glycosylphosphotidylinositol (GPI)-anchored proteins normally uniformly distributed in the parasite plasma membrane, coalesced into clusters. These alterations were not observed following drug treatment of P. falciparum parasites adapted to grow in a low [Na(+)] growth medium. Both cholesterol acquisition and MSP1 coalescence were reversible upon the removal of the drugs, implicating an active process of cholesterol exclusion from trophozoites that we hypothesize is inhibited by high [Na(+)](i). Electron microscopy of drug-treated trophozoites revealed substantial morphological changes normally seen at the later schizont stage including the appearance of partial inner membrane complexes, dense organelles that resemble “rhoptries” and apparent nuclear division. Together these results suggest that [Na(+)](i) disruptor drugs by altering levels of cholesterol in the parasite, dysregulate trophozoite to schizont development and cause parasite demise. Public Library of Science 2016-05-26 /pmc/articles/PMC4881962/ /pubmed/27227970 http://dx.doi.org/10.1371/journal.ppat.1005647 Text en © 2016 Das et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Das, Sudipta
Bhatanagar, Suyash
Morrisey, Joanne M.
Daly, Thomas M.
Burns, James M.
Coppens, Isabelle
Vaidya, Akhil B.
Na(+) Influx Induced by New Antimalarials Causes Rapid Alterations in the Cholesterol Content and Morphology of Plasmodium falciparum
title Na(+) Influx Induced by New Antimalarials Causes Rapid Alterations in the Cholesterol Content and Morphology of Plasmodium falciparum
title_full Na(+) Influx Induced by New Antimalarials Causes Rapid Alterations in the Cholesterol Content and Morphology of Plasmodium falciparum
title_fullStr Na(+) Influx Induced by New Antimalarials Causes Rapid Alterations in the Cholesterol Content and Morphology of Plasmodium falciparum
title_full_unstemmed Na(+) Influx Induced by New Antimalarials Causes Rapid Alterations in the Cholesterol Content and Morphology of Plasmodium falciparum
title_short Na(+) Influx Induced by New Antimalarials Causes Rapid Alterations in the Cholesterol Content and Morphology of Plasmodium falciparum
title_sort na(+) influx induced by new antimalarials causes rapid alterations in the cholesterol content and morphology of plasmodium falciparum
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881962/
https://www.ncbi.nlm.nih.gov/pubmed/27227970
http://dx.doi.org/10.1371/journal.ppat.1005647
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