The Malaria Parasite's Lactate Transporter PfFNT Is the Target of Antiplasmodial Compounds Identified in Whole Cell Phenotypic Screens

PLoS Pathogens

Malcolm J. McConville¹  Simon A. Cobbold¹  Kiaran Kirk²  Sanduni V. Hapuarachchi²  Rowena E. Martin²  Sarah H. Shafik²  Adele M. Lehane²  Adelaide S. M. Dennis² 

[1] Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, VIC, Australia;Research School of Biology, Australian National University, Canberra, ACT, Australia

关键词: Malarial parasites;    Red blood cells;    Parasitic diseases;    Xenopus oocytes;    Transport inhibition assay;    Malaria;    Plasmodium;    Metabolites;   

DOI  :  10.1371/journal.ppat.1006180

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY