Abstract
The emerging resistance to quinine jeopardizes the efficacy of a drug that has been used in the treatment of malaria for several centuries. To identify factors contributing to differential quinine responses in the human malaria parasite Plasmodium falciparum, we have conducted comparative quantitative trait locus analyses on the susceptibility to quinine and also its stereoisomer quinidine, and on the initial and steady-state intracellular drug accumulation levels in the F1 progeny of a genetic cross. These data, together with genetic screens of field isolates and laboratory strains associated differential quinine and quinidine responses with mutated pfcrt, a segment on chromosome 13, and a novel candidate gene, termed MAL7P1.19 (encoding a HECT ubiquitin ligase). Despite a strong likelihood of association, episomal transfections demonstrated a role for the HECT ubiquitin-protein ligase in quinine and quinidine sensitivity in only a subset of genetic backgrounds, and here the changes in IC50 values were moderate (approximately 2-fold). These data show that quinine responsiveness is a complex genetic trait with multiple alleles playing a role and that more experiments are needed to unravel the role of the contributing factors.
Highlights
Quinine, an active ingredient of cinchona bark, is an important drug in the pharmacopoeia against malaria, an infectious disease that causes an estimated 219 million clinical cases and 0.66 million deaths annually [1]
Novel quantitative trait loci (QTL) on chromosome 7 linked to differential quinine and quinidine responses
In a previous study we have shown that the P. falciparum clone HB3 accumulated with time significantly more [3H]-quinine and [3H]-quinidine from external concentrations of 40 nM than did the P. falciparum clone Dd2 [21]
Summary
An active ingredient of cinchona bark, is an important drug in the pharmacopoeia against malaria, an infectious disease that causes an estimated 219 million clinical cases and 0.66 million deaths annually [1]. A progressive loss in responsiveness of the human malaria parasite Plasmodium falciparum to quinine has been observed, in Southeast Asia [3,4,5] where cases of quinine treatment failure regularly occur, and in Latin American and Africa [6,7,8,9]. In spite of quinine’s pharmaceutical importance, very little is known about its antimalarial mode of action or the mechanism of resistance. The lack of information, the paucity of genetic markers predictive of quinine resistance, complicates the molecular surveillance of quinine resistant P. falciparum strains and jeopardizes efforts to preserve the efficacy of this very valuable drug
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