Combining Stage Specificity and Metabolomic Profiling to Advance Antimalarial Drug Discovery

James M. Murithi, Edward S. Owen, Eva S. Istvan, Marcus C.S. Lee, Sabine Ottilie, Kelly Chibale, Daniel E. Goldberg, Elizabeth A. Winzeler, Manuel Llinás, David A. Fidock (Lead / Corresponding author), Manu Vanaerschot (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

52 Citations (Scopus)
26 Downloads (Pure)


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. Murithi et al. designed a high-throughput assay to profile the Plasmodium falciparum asexual blood stage parasites against which antimalarial candidates are maximally active. These data combined with metabolomics fingerprinting provide valuable insights into the mode of action of clinical and experimental antimalarials, and helped prioritize compounds for further development.

Original languageEnglish
Pages (from-to)158-171.e3
JournalCell Chemical Biology
Issue number2
Early online date5 Dec 2019
Publication statusPublished - 20 Feb 2020


  • asexual blood stages
  • drug resistance
  • hemoglobin catabolism
  • malaria
  • metabolomics
  • mitochondria
  • mode of action
  • Plasmodium falciparum
  • target identification

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry


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