Identification of targets and mechanisms of resistance to imatinib and quinine using a molecular systems biology approach

摘要

Saccharomyces cerevisiae provides an excellent eukary-otic model for biomedical and medicinal research. In this article, yeast was applied in pharmacological studies to identify new targets and mechanisms of action of drugs, as well as pathways involved in drug resistance. The work here presented is focused on two distinct drugs: the traditional anti-malarial quinine, and the paradigmatic anti-cancer imatinib. Several genome-wide approaches were employed, ranging from transcriptomics to chemogenomics and quantitative proteomics. The main results that stem from this work include the identification of potential new targets and modes of action for the two drugs studied. In particular, the highly conserved yeast vacuolar H⁺-ATPase was shown to be inhibited by imatinib, both in vivo and in vitro, suggesting that vacuolar function is a novel imatinib target, while quinine was found to inhibit the uptake of glucose into yeast cells following a competitive inhibition kinetic model. These findings might have an important parallel in the malaria parasite biology, where glucose uptake is vital and mediated by PfHT1, a single-copy transporter highly homologous to yeasts.