Variation among Plasmodium falciparum Strains in Their Reliance on Mitochondrial Electron Transport Chain Function

• DOI: 10.1128/ec.05049-11
• Publication Date: 2011-06-18T02:50:01Z
• Authors: Hangjun Ke; Joanne M. Morrisey; Suresh M. Ganesan; Heather J. Painter; Michael W. Mather; Akhil B. Vaidya
• Keywords: Atovaquone; Dihydroorotate Dehydrogenase; Pyrimidine metabolism

Previous studies demonstrated that Plasmodium falciparum strain D10 became highly resistant to the mitochondrial electron transport chain (mtETC) inhibitor atovaquone when mtETC was decoupled from pyrimidine biosynthesis pathway by expressing fumarate-dependent (ubiquinone-independent) yeast dihydroorotate dehydrogenase (yDHODH) in parasites. To investigate requirement for activity P. with different genetic backgrounds, we integrated a single copy of yDHODH gene into genomes D10attB, 3D7attB, Dd2attB, and HB3attB strains parasite. The equally expressed all transgenic lines. All four lines showed strong resistance standard short-term growth inhibition assays. During longer term atovaquone, D10attB-yDHODH 3D7attB-yDHODH parasites remained fully resistant, but Dd2attB-yDHODH HB3attB-yDHODH lost their tolerance drug after 3 4 days exposure. No differences were found, however, responses among these Plasmodium-specific DHODH DSM1 either short- or long-term exposures. Thus, works well as selective agent parasite transfected gene, whereas some We found ubiquinone analog decylubiquinone substantially reversed during extended growth. conclude there are strain-specific strains, suggesting that, erythrocytic stages parasite, ubiquinone-dependent activities other than those dispensable essential others.