Diverse antimalarials from wholecell phenotypic screens disrupt malaria parasite ion and volume homeostasis
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Dennis, Adelaide; Rosling, James; Lehane, Adele; Kirk, Kiaran
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...[Show more]
dc.contributor.author | Dennis, Adelaide | |
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dc.contributor.author | Rosling, James | |
dc.contributor.author | Lehane, Adele | |
dc.contributor.author | Kirk, Kiaran | |
dc.date.accessioned | 2019-04-13T06:27:15Z | |
dc.date.available | 2019-04-13T06:27:15Z | |
dc.identifier.issn | 2045-2322 | |
dc.identifier.uri | http://hdl.handle.net/1885/159582 | |
dc.description.abstract | 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 | |
dc.description.sponsorship | This work was supported by a Project Grant (1042272) from the Australian National Health and Medical Research Council and by Australian Research Council Linkage Project Grant LP150101226. A.M.L. is the recipient of an Australian Research Council Discovery Early Career Researcher Award (DE160101035) | |
dc.format.mimetype | application/pdf | |
dc.language.iso | en_AU | |
dc.publisher | Nature Publishing Group | |
dc.rights | Author/s retain copyright | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.source | Scientific Reports | |
dc.title | Diverse antimalarials from wholecell phenotypic screens disrupt malaria parasite ion and volume homeostasis | |
dc.type | Journal article | |
local.description.notes | Imported from ARIES | |
local.identifier.citationvolume | 8 | |
dc.date.issued | 2018 | |
local.identifier.absfor | 060599 - Microbiology not elsewhere classified | |
local.identifier.ariespublication | u4008405xPUB147 | |
local.type.status | Published Version | |
local.contributor.affiliation | Dennis, Adelaide, College of Science, ANU | |
local.contributor.affiliation | Rosling, James, College of Science, ANU | |
local.contributor.affiliation | Lehane, Adele, College of Science, ANU | |
local.contributor.affiliation | Kirk, Kiaran, College of Science, ANU | |
local.bibliographicCitation.issue | 8795 | |
local.identifier.doi | 10.1038/s41598-018-26819-1 | |
local.identifier.absseo | 920101 - Blood Disorders | |
dc.date.updated | 2019-03-12T07:26:17Z | |
local.identifier.scopusID | 2-s2.0-85048408515 | |
dcterms.accessRights | Open Access | |
dc.rights.license | 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/. © Te Author(s) 2018 | |
Collections | ANU Research Publications |
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