Combining Stage Specificity and Metabolomic Profiling to Advance Antimalarial Drug Discovery

Cell Chem Biol. 2020 Feb 20;27(2):158-171.e3. doi: 10.1016/j.chembiol.2019.11.009. Epub 2019 Dec 5.


We report detailed susceptibility profiling of asexual blood stages of the malaria parasite Plasmodium falciparum to clinical and experimental antimalarials, combined with metabolomic fingerprinting. Results revealed a variety of stage-specific and metabolic profiles that differentiated the modes of action of clinical antimalarials including chloroquine, piperaquine, lumefantrine, and mefloquine, and identified late trophozoite-specific peak activity and stage-specific biphasic dose-responses for the mitochondrial inhibitors DSM265 and atovaquone. We also identified experimental antimalarials hitting previously unexplored druggable pathways as reflected by their unique stage specificity and/or metabolic profiles. These included several ring-active compounds, ones affecting hemoglobin catabolism through distinct pathways, and mitochondrial inhibitors with lower propensities for resistance than either DSM265 or atovaquone. This approach, also applicable to other microbes that undergo multiple differentiation steps, provides an effective tool to prioritize compounds for further development within the context of combination therapies.

Keywords: Plasmodium falciparum; asexual blood stages; drug resistance; hemoglobin catabolism; malaria; metabolomics; mitochondria; mode of action; target identification.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimalarials / chemistry
  • Antimalarials / metabolism
  • Antimalarials / pharmacology*
  • Atovaquone / chemistry
  • Atovaquone / metabolism
  • Atovaquone / pharmacology
  • Drug Design
  • Electron Transport Chain Complex Proteins / antagonists & inhibitors
  • Electron Transport Chain Complex Proteins / metabolism
  • Humans
  • Life Cycle Stages / drug effects
  • Malaria, Falciparum / drug therapy
  • Malaria, Falciparum / parasitology
  • Malaria, Falciparum / pathology
  • Metabolome / drug effects*
  • Metabolomics*
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / growth & development
  • Plasmodium falciparum / metabolism
  • Quinolines / chemistry
  • Quinolines / metabolism
  • Quinolines / pharmacology


  • Antimalarials
  • Electron Transport Chain Complex Proteins
  • Quinolines
  • piperaquine
  • Atovaquone