title: Atovaquone tolerance in Plasmodium falciparum parasites selected for high-level resistance to a dihydroorotate dehydrogenase inhibitor.
abstract: 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.
authors.affiliation: Departments of Chemistry and Global Health, University of Washington, Seattle, Washington, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Guler
authors.affiliation: Departments of Chemistry and Global Health, University of Washington, Seattle, Washington, USA.
authors.forename: John
authors.initials: J
authors.lastname: White
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Phillips
authors.affiliation: Departments of Chemistry and Global Health, University of Washington, Seattle, Washington, USA rathod@chem.washington.edu.
authors.forename: Pradipsinh K
authors.initials: PK
authors.lastname: Rathod
mesh_terms: D000962:Antimalarials / Q000494:pharmacology*; D053626:Atovaquone / Q000494:pharmacology*; D000090722:Dihydroorotate Dehydrogenase; D004338:Drug Combinations; D004351:Drug Resistance; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors*; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D002727:Proguanil / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D000090722:Dihydroorotate Dehydrogenase; D004338:Drug Combinations; C109496:atovaquone, proguanil drug combination; D044925:Oxidoreductases Acting on CH-CH Group Donors; D002727:Proguanil; D053626:Atovaquone