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Diverse antimalarials from whole-cell phenotypic screens disrupt malaria parasite ion and volume homeostasis

Four hundred structurally diverse drug-like compounds comprising the Medicines for Malaria Venture’s ‘Pathogen Box’ were screened for their effect on a range of physiological parameters in asexual blood-stage malaria (Plasmodium falciparum) parasites. Eleven of these compounds were found to perturb...

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Autores principales: Dennis, Adelaide S. M., Rosling, James E. O., Lehane, Adele M., Kirk, Kiaran
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995868/
https://www.ncbi.nlm.nih.gov/pubmed/29892073
http://dx.doi.org/10.1038/s41598-018-26819-1
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author Dennis, Adelaide S. M.
Rosling, James E. O.
Lehane, Adele M.
Kirk, Kiaran
author_facet Dennis, Adelaide S. M.
Rosling, James E. O.
Lehane, Adele M.
Kirk, Kiaran
author_sort Dennis, Adelaide S. M.
collection PubMed
description Four hundred structurally diverse drug-like compounds comprising the Medicines for Malaria Venture’s ‘Pathogen Box’ were screened for their effect on a range of physiological parameters in asexual blood-stage malaria (Plasmodium falciparum) parasites. Eleven of these compounds were found to perturb parasite Na(+), pH and volume in a manner consistent with inhibition of the putative Na(+) efflux P-type ATPase PfATP4. All eleven compounds fell within the subset of 125 compounds included in the Pathogen Box on the basis of their having been identified as potent inhibitors of the growth of asexual blood-stage P. falciparum parasites. All eleven compounds inhibited the Na(+)-dependent ATPase activity of parasite membranes and showed reduced efficacy against parasites carrying mutations in PfATP4. This study increases the number of chemically diverse structures known to show a ‘PfATP4-associated’ phenotype, and adds to emerging evidence that a high proportion (7–9%) of the structurally diverse antimalarial compounds identified in whole cell phenotypic screens share the same mechanism of action, exerting their antimalarial effect via an interaction with PfATP4.
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spelling pubmed-59958682018-06-21 Diverse antimalarials from whole-cell phenotypic screens disrupt malaria parasite ion and volume homeostasis Dennis, Adelaide S. M. Rosling, James E. O. Lehane, Adele M. Kirk, Kiaran Sci Rep Article Four hundred structurally diverse drug-like compounds comprising the Medicines for Malaria Venture’s ‘Pathogen Box’ were screened for their effect on a range of physiological parameters in asexual blood-stage malaria (Plasmodium falciparum) parasites. Eleven of these compounds were found to perturb parasite Na(+), pH and volume in a manner consistent with inhibition of the putative Na(+) efflux P-type ATPase PfATP4. All eleven compounds fell within the subset of 125 compounds included in the Pathogen Box on the basis of their having been identified as potent inhibitors of the growth of asexual blood-stage P. falciparum parasites. All eleven compounds inhibited the Na(+)-dependent ATPase activity of parasite membranes and showed reduced efficacy against parasites carrying mutations in PfATP4. This study increases the number of chemically diverse structures known to show a ‘PfATP4-associated’ phenotype, and adds to emerging evidence that a high proportion (7–9%) of the structurally diverse antimalarial compounds identified in whole cell phenotypic screens share the same mechanism of action, exerting their antimalarial effect via an interaction with PfATP4. Nature Publishing Group UK 2018-06-11 /pmc/articles/PMC5995868/ /pubmed/29892073 http://dx.doi.org/10.1038/s41598-018-26819-1 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Dennis, Adelaide S. M.
Rosling, James E. O.
Lehane, Adele M.
Kirk, Kiaran
Diverse antimalarials from whole-cell phenotypic screens disrupt malaria parasite ion and volume homeostasis
title Diverse antimalarials from whole-cell phenotypic screens disrupt malaria parasite ion and volume homeostasis
title_full Diverse antimalarials from whole-cell phenotypic screens disrupt malaria parasite ion and volume homeostasis
title_fullStr Diverse antimalarials from whole-cell phenotypic screens disrupt malaria parasite ion and volume homeostasis
title_full_unstemmed Diverse antimalarials from whole-cell phenotypic screens disrupt malaria parasite ion and volume homeostasis
title_short Diverse antimalarials from whole-cell phenotypic screens disrupt malaria parasite ion and volume homeostasis
title_sort diverse antimalarials from whole-cell phenotypic screens disrupt malaria parasite ion and volume homeostasis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995868/
https://www.ncbi.nlm.nih.gov/pubmed/29892073
http://dx.doi.org/10.1038/s41598-018-26819-1
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