Abstract
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.
Highlights
The most virulent malaria parasite, Plasmodium falciparum, was responsible for the majority of the 214 million malaria cases and 438,000 malaria-attributable deaths estimated to have occurred in 2015 [1]
The emergence and spread of Plasmodium falciparum strains resistant to leading antimalarial drugs has intensified the need to discover and develop drugs that kill the parasite via new mechanisms
We identified fifteen compounds that decrease the pH inside the parasite, and determined the mechanism by which two of these, MMV007839 and MMV000972, disrupt pH and kill the parasite
Summary
The most virulent malaria parasite, Plasmodium falciparum, was responsible for the majority of the 214 million malaria cases and 438,000 malaria-attributable deaths estimated to have occurred in 2015 [1]. Significant progress has been made in recent years in developing new antimalarials [3]; many of the compounds under development are structurally related to previous or current antimalarial drugs and there is an urgent need to identify novel lead-drug compounds that act on hitherto unexploited parasite targets and create improved options for resistance-deterring combination therapies. Such therapies should, ideally, contain at least two drugs that act on separate targets [4]. Determining the mechanisms of action of these antiplasmodial compounds has the potential to uncover aspects of P. falciparum biology that can be exploited as drug targets
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