The Plasmodium lactate/H+ transporter PfFNT is essential and druggable in vivo.
journal contributionposted on 2023-08-22, 11:34 authored by Heledd Davies, Bärbel Bergmann, Philipp Walloch, Cornelius Nerlich, Christian Hansen, Sergio Wittlin, Tobias Spielmann, Moritz Treeck, Eric Beitz
Malaria parasites in the blood stage express a single transmembrane transport protein for the release of the glycolytic end product l-lactate/H+ from the cell. This transporter is a member of the strictly microbial formate-nitrite transporter (FNT) family and a novel putative drug target. Small, drug-like FNT inhibitors potently block lactate transport and kill Plasmodium falciparum parasites in culture. The protein structure of Plasmodium falciparum FNT (PfFNT) in complex with the inhibitor has been resolved and confirms its previously predicted binding site and its mode of action as a substrate analog. Here, we investigated the mutational plasticity and essentiality of the PfFNT target on a genetic level, and established its in vivo druggability using mouse malaria models. We found that, besides a previously identified PfFNT G107S resistance mutation, selection of parasites at 3 × IC50 (50% inhibitory concentration) gave rise to two new point mutations affecting inhibitor binding: G21E and V196L. Conditional knockout and mutation of the PfFNT gene showed essentiality in the blood stage, whereas no phenotypic defects in sexual development were observed. PfFNT inhibitors mainly targeted the trophozoite stage and exhibited high potency in P. berghei- and P. falciparum-infected mice. Their in vivo activity profiles were comparable to that of artesunate, demonstrating strong potential for the further development of PfFNT inhibitors as novel antimalarials.
Crick (Grant ID: CC2132, Grant title: Treeck CC2132)
antimalarial agentsantimalarialsformate-nitrite transporterlactatemalariaPlasmodiumprotonresistanceAnimalsMiceMonocarboxylic Acid TransportersPlasmodium falciparumMalaria, FalciparumAntimalarialsParasitesLactatesPlasmodium bergheiProtozoan ProteinsTreeck CC21320605 Microbiology1108 Medical Microbiology1115 Pharmacology and Pharmaceutical SciencesMicrobiology