A drug-selected Plasmodium falciparum lacking the need for conventional electron transport.
Mitochondrial electron transport is essential for survival in Plasmodium falciparum, making the cytochrome (cyt) bc(1) complex an attractive target for antimalarial drug development. Here we report that P. falciparum cultivated in the presence of a novel cyt bc(1) inhibitor underwent a fundamental transformation in biochemistry to a phenotype lacking a requirement for electron transport through the cyt bc(1) complex. Growth of the drug-selected parasite clone (SB1-A6) is robust in the presence of diverse cyt bc(1) inhibitors, although electron transport is fully inhibited by these same agents. This transformation defies expected molecular-based concepts of drug resistance, has important implications for the study of cyt bc(1) as an antimalarial drug target, and may offer a glimpse into the evolutionary future of Plasmodium.
Smilkstein
Martin J
MJ
Medical Research Service, Department of Veterans Affairs Medical Center, Portland, OR 97239, USA. smilkste@ohsu.edu
Forquer
Isaac
I
Kanazawa
Atsuko
A
Kelly
Jane Xu
JX
Winter
Rolf W
RW
Hinrichs
David J
DJ
Kramer
David M
DM
Riscoe
Michael K
MK
D000166:Acridines / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D053626:Atovaquone / Q000494:pharmacology; D004351:Drug Resistance / Q000235:genetics; D004579:Electron Transport; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D012641:Selection, Genetic; D012692:Serial Passage
D000166:Acridines; D000962:Antimalarials; D004791:Enzyme Inhibitors; D014450:Electron Transport Complex III; D053626:Atovaquone