Plasmodium falciparum Cyclic Amine Resistance Locus (PfCARL), a Resistance Mechanism for Two Distinct Compound Classes

MMV007564
is a novel antimalarial benzimidazolyl piperidine chemotype
identified in cellular screens. To identify the genetic determinant
of MMV007564 resistance, parasites were cultured in the presence of
the compound to generate resistant lines. Whole genome sequencing
revealed distinct mutations in the gene named Plasmodium
falciparum cyclic amine resistance locus (pfcarl), encoding a conserved protein of unknown function.
Mutations in pfcarl are strongly associated with
resistance to a structurally unrelated class of compounds, the imidazolopiperazines,
including KAF156, currently in clinical trials. Our data demonstrate
that pfcarl mutations confer resistance to two distinct
compound classes, benzimidazolyl piperidines and imidazolopiperazines.
However, MMV007564 and the imidazolopiperazines, KAF156 and GNF179,
have different timings of action in the asexual blood stage and different
potencies against the liver and sexual blood stages. These data suggest
that pfcarl is a multidrug-resistance gene rather
than a common target for benzimidazolyl piperidines and imidazolopiperazines.