Atovaquone tolerance in Plasmodium falciparum parasites selected for high-level resistance to a dihydroorotate dehydrogenase inhibitor

Antimicrob Agents Chemother. 2015 Jan;59(1):686-9. doi: 10.1128/AAC.02347-14. Epub 2014 Oct 20.


Atovaquone is a component of Malarone, a widely prescribed antimalarial combination, that targets malaria respiration. Here we show that parasites with high-level resistance to an inhibitor of dihydroorotate dehydrogenase demonstrate unexpected atovaquone tolerance. Fortunately, the tolerance is diminished with proguanil, the second partner in Malarone. It is important to understand such "genetic cross talk" between respiration and pyrimidine biosynthesis since many antimalarial drug development programs target these two seemingly independent pathways.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antimalarials / pharmacology*
  • Atovaquone / pharmacology*
  • Dihydroorotate Dehydrogenase
  • Drug Combinations
  • Drug Resistance
  • Oxidoreductases Acting on CH-CH Group Donors / antagonists & inhibitors*
  • Parasitic Sensitivity Tests
  • Plasmodium falciparum / drug effects*
  • Proguanil / pharmacology


  • Antimalarials
  • Dihydroorotate Dehydrogenase
  • Drug Combinations
  • atovaquone, proguanil drug combination
  • Oxidoreductases Acting on CH-CH Group Donors
  • Proguanil
  • Atovaquone