Quinine has been employed in the treatment of malaria for centuries and is still used against severe Plasmodium falciparum malaria. However, its interactions with the parasite remain poorly understood and subject to debate. In this study, we used the eukaryotic model Saccharomyces cerevisiae to better understand quinine's mode of action and the mechanisms underlying the cell response to the drug. We obtained a transcriptomic profile of the yeast early response to quinine, evidencing a marked activation of genes involved in the low-glucose response (e.g. CAT8, ADR1, MAL33, MTH1 and SNF3). We used a low-inhibitory quinine concentration with no detectable effect over plasma membrane function, consistent with the absence of a general nutrient starvation response and suggesting that quinine-induced glucose limitation is a specific response. We have further shown that transport of [(14)C]-glucose is inhibited by quinine, with kinetic data indicating competitive inhibition. Also, tested mutant strains deleted for genes encoding high and low-affinity hexose transporters (HXT1 - HXT5, HXT8 and HXT10) exhibit resistance phenotypes, correlating with reduced levels of quinine accumulation in the mutants examined. These results suggest that the hexose transporters are facilitators of quinine uptake in S. cerevisiae, possibly through a competitive inhibition mechanism. Interestingly, P. falciparum is highly dependent on glucose uptake, which is mediated by the single-copy transporter PfHT1, a protein with high homology to yeast's hexose transporters. We propose that PfHT1 is an interesting candidate quinine target, eventually involved in quinine import in P. falciparum, an uptake mechanism postulated in recent studies through still unidentified importer(s).
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