Antimalarial pantothenamide metabolites target acetyl-coenzyme A biosynthesis in Plasmodium falciparum

Sci Transl Med. 2019 Sep 18;11(510):eaas9917. doi: 10.1126/scitranslmed.aas9917.


Malaria eradication is critically dependent on new therapeutics that target resistant Plasmodium parasites and block transmission of the disease. Here, we report that pantothenamide bioisosteres were active against blood-stage Plasmodium falciparum parasites and also blocked transmission of sexual stages to the mosquito vector. These compounds were resistant to degradation by serum pantetheinases, showed favorable pharmacokinetic properties, and cleared parasites in a humanized mouse model of P. falciparum infection. Metabolomics revealed that coenzyme A biosynthetic enzymes converted pantothenamides into coenzyme A analogs that interfered with parasite acetyl-coenzyme A anabolism. Resistant parasites generated in vitro showed mutations in acetyl-coenzyme A synthetase and acyl-coenzyme A synthetase 11. Introduction and reversion of these mutations in P. falciparum using CRISPR-Cas9 gene editing confirmed the roles of these enzymes in the sensitivity of the malaria parasites to pantothenamides. These pantothenamide compounds with a new mode of action may have potential as drugs against malaria parasites.

Publication types

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

MeSH terms

  • Acetyl Coenzyme A / biosynthesis*
  • Animals
  • Antimalarials / chemistry
  • Antimalarials / pharmacokinetics
  • Antimalarials / pharmacology*
  • Biosynthetic Pathways / drug effects*
  • Disease Models, Animal
  • Drug Resistance / drug effects
  • Humans
  • Malaria, Falciparum / parasitology
  • Malaria, Falciparum / transmission
  • Male
  • Mice, Inbred BALB C
  • Mutation / genetics
  • Pantothenic Acid / analogs & derivatives*
  • Pantothenic Acid / chemistry
  • Pantothenic Acid / pharmacology*
  • Parasitemia / drug therapy
  • Parasites / drug effects
  • Parasites / metabolism
  • Plasmodium falciparum / metabolism*
  • Protozoan Proteins / genetics
  • Reproduction, Asexual / drug effects
  • Treatment Outcome
  • Trophozoites / drug effects
  • Trophozoites / metabolism


  • Antimalarials
  • Protozoan Proteins
  • Pantothenic Acid
  • pantothenamide
  • Acetyl Coenzyme A