PLoS Pathog. doi:10.1371/journal.ppat.1006180 (2017)

The human malaria parasite Plasmodium falciparum has developed resistance to most existing drugs, so drugs with new mechanisms of action are urgently needed. One parasite pathway that is underexplored as a potential therapeutic target is that involved in the generation of ATP. The parasite takes up glucose and converts it via glycolysis to lactate, generating ATP in the process. The lactate end product is exported from the parasite via a proton-coupled (pH-dependent) transporter. Hapuarachchi et al. screened a curated collection of antiplasmodial compounds for their effect on parasite pH and identified 15 compounds that acidified the parasite. Monitoring the acidification under conditions in which glycolysis was either active or turned off revealed that 2 of the 15 hits exerted their effect on pH through the inhibition of proton-coupled lactate efflux. Parasites selected for resistance to one of these two compounds that were also resistant to the otheR had a mutation in the lactate–H+ transporter PfFNT. The compounds inhibited lactate transport both in isolated parasites and in Xenopus oocytes expressing the PfFNT transporter. The resistance-associated mutation in PfFNT reduced inhibition of transport in both systems. This study highlights the potential of the lactate transporter PfFNT as an antimalarial drug target.