A drug-selected Plasmodium falciparum lacking the need for conventional electron transport
2008
Smilkstein, Martin J. | Forquer, Isaac | Kanazawa, Atsuko | Kelly, Jane XU. | Winter, Rolf W. | Hinrichs, David J. | Kramer, David M. | Riscoe, Michael K.
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.
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