Abstract
BackgroundFungal infections are an emerging health risk, especially those involving yeast that are resistant to antifungal agents. To understand the range of mechanisms by which yeasts can respond to anti-fungals, we compared gene expression patterns across three evolutionarily distant species - Saccharomyces cerevisiae, Candida glabrata and Kluyveromyces lactis - over time following fluconazole exposure.ResultsConserved and diverged expression patterns were identified using a novel soft clustering algorithm that concurrently clusters data from all species while incorporating sequence orthology. The analysis suggests complementary strategies for coping with ergosterol depletion by azoles - Saccharomyces imports exogenous ergosterol, Candida exports fluconazole, while Kluyveromyces does neither, leading to extreme sensitivity. In support of this hypothesis we find that only Saccharomyces becomes more azole resistant in ergosterol-supplemented media; that this depends on sterol importers Aus1 and Pdr11; and that transgenic expression of sterol importers in Kluyveromyces alleviates its drug sensitivity.ConclusionsWe have compared the dynamic transcriptional responses of three diverse yeast species to fluconazole treatment using a novel clustering algorithm. This approach revealed significant divergence among regulatory programs associated with fluconazole sensitivity. In future, such approaches might be used to survey a wider range of species, drug concentrations and stimuli to reveal conserved and divergent molecular response pathways.
Highlights
Fungal infections are an emerging health risk, especially those involving yeast that are resistant to antifungal agents
We examined the phenotypic response of these species to a range of concentrations of fluconazole (Additional file 1: Testing Fluconazole Susceptibility), a triazole antifungal drug commonly used in the treatment and prevention of superficial and systemic fungal infections [4]
We found that Kluyveromyces lactis (Kl) was approximately 70 times more sensitive to fluconazole than Saccharomyces cerevisiae (Sc) and Candida glabrata (Cg), with a 50% inhibitory concentration of 0.06 μg/ml versus 4.0 μg/ml for both Sc and Cg (Figure S1 in Additional file 1)
Summary
Fungal infections are an emerging health risk, especially those involving yeast that are resistant to antifungal agents. The most common treatment for fungal infections is the family of chemical compounds known as the azoles, which interfere with formation of the cell membrane by inhibiting synthesis of ergosterol [4]. The fungal response to azoles has been most often studied in yeast [5,7,12,13,14,15,16,17], primarily through analysis of standard laboratory strains of Candida [12,13,18] or Saccharomyces [14,16,17] or their resistant clinical isolates [2,12,15,19]. This work has revealed a number of resistance and response mechanisms that can be invoked to protect cells from drugs, including mutations to drug efflux pumps or their regulators [2,12,20,21], mutations to ergosterol synthesis enzymes [20], duplication of the fluconazole target Erg11 [18], and a possible role for Hsp90 [15,22]
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