A drug-selected Plasmodium falciparum lacking the need for conventional electron transport

Abstract

Mitochondrial electron transport is essential for survival in Plasmodium falciparum, making the cytochrome (cyt) bc1 complex an attractive target for antimalarial drug development. Here we report that P. falciparum cultivated in the presence of a novel cyt bc1 inhibitor underwent a fundamental transformation in biochemistry to a phenotype lacking a requirement for electron transport through the cyt bc1 complex. Growth of the drug-selected parasite clone (SB1-A6) is robust in the presence of diverse cyt bc1 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 bc1 as an antimalarial drug target, and may offer a glimpse into the evolutionary future of Plasmodium.