Mechanistic insights into dual-active liver and blood-stage antiplasmodials.

ABSTRACT: The identification of novel antimalarials with activity against both the liver and blood stages of the parasite lifecycle would have the dual benefit of prophylactic and curative potential. However, one challenge of leveraging chemical hits from phenotypic screens is subsequent target identification. Here, we use in vitro evolution of resistance to investigate nine compounds from the Tres Cantos Antimalarial Set (TCAMS) with dual liver and asexual blood stage activity. We succeeded in eliciting resistance to four compounds, yielding mutations in acetyl CoA synthetase (AcAS), cytoplasmic isoleucine tRNA synthetase (cIRS), and protein kinase G (PKG), respectively. Using a combination of CRISPR editing and in vitro activity assays with recombinant proteins, we validate these as

SUBMITTER: Rawat M 

PROVIDER: S-EPMC12802172 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature