Metabolic Differentiation of Saccharomyces cerevisiae by Ketoconazole Treatment

Abstract

Azole fungicides are one of the most wide-spread antifungal compounds in agriculture and pharmaceutical applications. Their major mode of action is the inhibition of ergosterol biosynthesis, giving depletion of ergosterol, precursors and abnormal steroids. However, metabolic consequences of such inhibition, other than steroidal metabolitesare not well established. Comprehensive metabolic profiles of Saccharomyces cerevisiae has been presented in this study. Wild type yeast was treated either with glucose as control or azole fungicide (ketoconazole). Both polar metabolites and lipids were analyzed with gas chromatographymass spectrometry. Approximately over 180 metabolites were characterized, among which 18 of them were accumulated or depleted by fungicide treatment. Steroid profile gives the most prominent differences, including the accumulation of lanosterol and the depletion of zymosterol and ergosterol. However, the polar metabolite profile was also highly different in pesticide treatment. The concentration of proline and its precursors, glutamate and ornithine were markedly reduced by ketoconazole. Lysine and glycine level was also decreased while the concentrations of serine and homoserine were increased. The overall metabolic profile indicates that azole fungicide treatment induces the depletion of many polar metabolites, which are important in stress response.

Multilocus resistance evolution to azole fungicides in fungal plant pathogen populations

“…). A metabolomics study showed the depletion of lysine and other polar metabolites as an important factor in the stress response of S. cerevisiae exposed to ketoconazole (Keum & Kim ). However, the functional link between lysine depletion and azole stress responses is unclear.…”

“…A genome-wide expression profile of Schizosaccharomyces pombe and Cryptococcus neoformans found SDH to be upregulated in response to exposure to clotrimazole and fluconazole, respectively (Florio et al 2011;Fang et al 2012). A metabolomics study showed the depletion of lysine and other polar metabolites as an important factor in the stress response of S. cerevisiae exposed to ketoconazole (Keum & Kim 2013). However, the functional link between lysine depletion and azole stress responses is unclear.…”