The Malaria Parasite's Lactate Transporter PfFNT Is the Target of Antiplasmodial Compounds Identified in Whole Cell Phenotypic Screens.
In this study the 'Malaria Box' chemical library comprising 400 compounds with antiplasmodial activity was screened for compounds that perturb the internal pH of the malaria parasite, Plasmodium falciparum. Fifteen compounds induced an acidification of the parasite cytosol. Two of these di...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2017-02-01
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| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1006180&type=printable |
| _version_ | 1826579509293350912 |
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| author | Sanduni V Hapuarachchi Simon A Cobbold Sarah H Shafik Adelaide S M Dennis Malcolm J McConville Rowena E Martin Kiaran Kirk Adele M Lehane |
| author_facet | Sanduni V Hapuarachchi Simon A Cobbold Sarah H Shafik Adelaide S M Dennis Malcolm J McConville Rowena E Martin Kiaran Kirk Adele M Lehane |
| author_sort | Sanduni V Hapuarachchi |
| collection | DOAJ |
| description | In this study the 'Malaria Box' chemical library comprising 400 compounds with antiplasmodial activity was screened for compounds that perturb the internal pH of the malaria parasite, Plasmodium falciparum. Fifteen compounds induced an acidification of the parasite cytosol. Two of these did so by inhibiting the parasite's formate nitrite transporter (PfFNT), which mediates the H+-coupled efflux from the parasite of lactate generated by glycolysis. Both compounds were shown to inhibit lactate transport across the parasite plasma membrane, and the transport of lactate by PfFNT expressed in Xenopus laevis oocytes. PfFNT inhibition caused accumulation of lactate in parasitised erythrocytes, and swelling of both the parasite and parasitised erythrocyte. Long-term exposure of parasites to one of the inhibitors gave rise to resistant parasites with a mutant form of PfFNT that showed reduced inhibitor sensitivity. This study provides the first evidence that PfFNT is a druggable antimalarial target. |
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| id | doaj.art-af29320f19f24b8b9d2b5dfd5482a5da |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2025-03-14T14:19:24Z |
| publishDate | 2017-02-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS Pathogens |
| spelling | doaj.art-af29320f19f24b8b9d2b5dfd5482a5da2025-02-27T05:31:47ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742017-02-01132e100618010.1371/journal.ppat.1006180The Malaria Parasite's Lactate Transporter PfFNT Is the Target of Antiplasmodial Compounds Identified in Whole Cell Phenotypic Screens.Sanduni V HapuarachchiSimon A CobboldSarah H ShafikAdelaide S M DennisMalcolm J McConvilleRowena E MartinKiaran KirkAdele M LehaneIn this study the 'Malaria Box' chemical library comprising 400 compounds with antiplasmodial activity was screened for compounds that perturb the internal pH of the malaria parasite, Plasmodium falciparum. Fifteen compounds induced an acidification of the parasite cytosol. Two of these did so by inhibiting the parasite's formate nitrite transporter (PfFNT), which mediates the H+-coupled efflux from the parasite of lactate generated by glycolysis. Both compounds were shown to inhibit lactate transport across the parasite plasma membrane, and the transport of lactate by PfFNT expressed in Xenopus laevis oocytes. PfFNT inhibition caused accumulation of lactate in parasitised erythrocytes, and swelling of both the parasite and parasitised erythrocyte. Long-term exposure of parasites to one of the inhibitors gave rise to resistant parasites with a mutant form of PfFNT that showed reduced inhibitor sensitivity. This study provides the first evidence that PfFNT is a druggable antimalarial target.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1006180&type=printable |
| spellingShingle | Sanduni V Hapuarachchi Simon A Cobbold Sarah H Shafik Adelaide S M Dennis Malcolm J McConville Rowena E Martin Kiaran Kirk Adele M Lehane The Malaria Parasite's Lactate Transporter PfFNT Is the Target of Antiplasmodial Compounds Identified in Whole Cell Phenotypic Screens. PLoS Pathogens |
| title | The Malaria Parasite's Lactate Transporter PfFNT Is the Target of Antiplasmodial Compounds Identified in Whole Cell Phenotypic Screens. |
| title_full | The Malaria Parasite's Lactate Transporter PfFNT Is the Target of Antiplasmodial Compounds Identified in Whole Cell Phenotypic Screens. |
| title_fullStr | The Malaria Parasite's Lactate Transporter PfFNT Is the Target of Antiplasmodial Compounds Identified in Whole Cell Phenotypic Screens. |
| title_full_unstemmed | The Malaria Parasite's Lactate Transporter PfFNT Is the Target of Antiplasmodial Compounds Identified in Whole Cell Phenotypic Screens. |
| title_short | The Malaria Parasite's Lactate Transporter PfFNT Is the Target of Antiplasmodial Compounds Identified in Whole Cell Phenotypic Screens. |
| title_sort | malaria parasite s lactate transporter pffnt is the target of antiplasmodial compounds identified in whole cell phenotypic screens |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1006180&type=printable |
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