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 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.
Research School of Biology, Australian National University, Canberra, ACT, Australia.
Sanduni V
SV
Hapuarachchi
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, VIC, Australia.
Simon A
SA
Cobbold
Research School of Biology, Australian National University, Canberra, ACT, Australia.
Sarah H
0000-0001-6503-3565
SH
Shafik
Research School of Biology, Australian National University, Canberra, ACT, Australia.
Adelaide S M
0000-0001-5473-629X
AS
Dennis
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, VIC, Australia.
Malcolm J
MJ
McConville
Research School of Biology, Australian National University, Canberra, ACT, Australia.
Rowena E
RE
Martin
Research School of Biology, Australian National University, Canberra, ACT, Australia.
Kiaran
0000-0002-5613-2622
K
Kirk
Research School of Biology, Australian National University, Canberra, ACT, Australia.
Adele M
AM
Lehane
D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002853:Chromatography, Liquid; D004353:Drug Evaluation, Preclinical; D004912:Erythrocytes / Q000469:parasitology*; D006801:Humans; D016778:Malaria, Falciparum / Q000378:metabolism* / Q000469:parasitology; D013058:Mass Spectrometry; D027501:Monocarboxylic Acid Transporters / Q000187:drug effects*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000378:metabolism / Q000469:parasitology; D015800:Protozoan Proteins / Q000378:metabolism; D014982:Xenopus laevis
D000962:Antimalarials; D027501:Monocarboxylic Acid Transporters; D015800:Protozoan Proteins