Plasmodium dihydrofolate reductase is a second enzyme target for the antimalarial action of triclosan

Sci Rep. 2018 Jan 18;8(1):1038. doi: 10.1038/s41598-018-19549-x.

Abstract

Malaria, caused by parasites of the genus Plasmodium, leads to over half a million deaths per year, 90% of which are caused by Plasmodium falciparum. P. vivax usually causes milder forms of malaria; however, P. vivax can remain dormant in the livers of infected patients for weeks or years before re-emerging in a new bout of the disease. The only drugs available that target all stages of the parasite can lead to severe side effects in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency; hence, there is an urgent need to develop new drugs active against blood and liver stages of the parasite. Different groups have demonstrated that triclosan, a common antibacterial agent, targets the Plasmodium liver enzyme enoyl reductase. Here, we provide 4 independent lines of evidence demonstrating that triclosan specifically targets both wild-type and pyrimethamine-resistant P. falciparum and P. vivax dihydrofolate reductases, classic targets for the blood stage of the parasite. This makes triclosan an exciting candidate for further development as a dual specificity antimalarial, which could target both liver and blood stages of the parasite.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimalarials / chemistry
  • Antimalarials / pharmacology*
  • Binding Sites
  • Enzyme Activation / drug effects
  • Folic Acid Antagonists / chemistry
  • Folic Acid Antagonists / pharmacology*
  • Models, Molecular
  • Molecular Conformation
  • Plasmodium / drug effects*
  • Plasmodium / enzymology*
  • Protein Binding
  • Structure-Activity Relationship
  • Tetrahydrofolate Dehydrogenase / chemistry
  • Tetrahydrofolate Dehydrogenase / metabolism*
  • Triclosan / chemistry
  • Triclosan / pharmacology*

Substances

  • Antimalarials
  • Folic Acid Antagonists
  • Triclosan
  • Tetrahydrofolate Dehydrogenase