The Malaria Parasite's Lactate Transporter PfFNT Is the Target of Antiplasmodial Compounds Identified in Whole Cell Phenotypic Screens
AuthorHapuarachchi, SV; Cobbold, SA; Shafik, SH; Dennis, ASM; McConville, MJ; Martin, RE; Kirk, K; Lehane, AM
Source TitlePLoS Pathogens
PublisherPUBLIC LIBRARY SCIENCE
AffiliationBiochemistry and Molecular Biology
Medical Biology (W.E.H.I.)
Document TypeJournal Article
CitationsHapuarachchi, S. V., Cobbold, S. A., Shafik, S. H., Dennis, A. S. M., McConville, M. J., Martin, R. E., Kirk, K. & Lehane, A. M. (2017). The Malaria Parasite's Lactate Transporter PfFNT Is the Target of Antiplasmodial Compounds Identified in Whole Cell Phenotypic Screens. PLOS PATHOGENS, 13 (2), https://doi.org/10.1371/journal.ppat.1006180.
Access StatusOpen Access
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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