Substrate-analogous inhibitors exert antimalarial action by targeting the Plasmodium lactate transporter PfFNT at nanomolar scale
Fig 5
Selection of resistant 3D7 parasites confirms PfFNT as the MMV007839 target.
(A) A single nucleotide exchange in the PfFNT gene of MMV007839 resistant 3D7 parasites. (B) Position of the resulting G107S mutation in the conserved L2 loop of the FNT family (numbering from PfFNT; set with TeXshade [21]). (C) Model of a PfFNT monomer [7] with position 107 shown as spheres (glycine in wildtype, left/center; G107S, right) and the L2/L5 loops shaded orange and blue, respectively. (D) Strongly reduced efficiency of MMV007839 on PfFNT G107S in yeast (black) and resistant parasites (red); dashed lines indicate efficiency on wildtype PfNT and parasites for comparison. (E) Confirmation of the MMV007839/FNT interaction by increase in efficiency on the Babesia bovis FNT by mutation of the naturally occurring serine to glycine at the resistance site. Errors denote S.E.M. from ≥ 3 replicates.