ABSTRACTQuinine has been employed in the treatment of malaria for centuries and is still used against severePlasmodium falciparummalaria. However, its interactions with the parasite remain poorly understood and subject to debate. In this study, we used theSaccharomyces cerevisiaeeukaryotic model 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's early response to quinine, evidencing a marked activation of genes involved in the low-glucose response (e.g.,CAT8,ADR1,MAL33,MTH1, andSNF3). We used a low inhibitory quinine concentration with no detectable effect on 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 [14C]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 (HXT1toHXT5,HXT8, andHXT10) 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 inS. cerevisiae, possibly through a competitive inhibition mechanism. Interestingly,P. falciparumis 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 possibly involved in quinine import inP. falciparum, an uptake mechanism postulated in recent studies to occur through a still-unidentified importer(s).