Modulation of yeast Erg1 expression and terbinafine susceptibility by iron bioavailability

Abstract

Ergosterol is a specific sterol component of yeast and fungal membranes.Its biosynthesis is one of the most effective targets for antifungal treatments.However, the emergent resistance to multiple sterol-based antifungal drugs emphasizes the need for new therapeutic approaches. The allylamine terbinafine, which selectively inhibits squalene epoxidase Erg1 within the ergosterol biosynthetic pathway, is mainly used to treat dermatomycoses, whereas its effectiveness in other fungal infections is limited. Given that ergosterol biosynthesis depends on iron as an essential cofactor, in this report, we used the yeast Saccharomyces cerevisiae to investigate how iron bioavailability influences Erg1 expression and terbinafine susceptibility. We observed that both chemical and genetic depletion of iron decrease ERG1 expression, leading to an increase in terbinafine susceptibility. Deletion of either ROX1 transcriptional repressor or CTH1 and CTH2 post-transcriptional repressors of ERG1 expression led to an increase in Erg1 protein levels and terbinafine resistance. On the contrary, overexpression of CTH2 led to the opposite effect, lowering Erg1 levels and increasing terbinafine susceptibility. Although strainspecific particularities exist, opportunistic pathogenic strains of S. cerevisiae displayed a response similar to the laboratory strain. These data indicate that iron bioavailability and particular regulatory factors could be used to modulate susceptibility to terbinafine. bs_bs_banner JORDÁ et al.

Metabolic Engineering for Efficient Synthesis of Patchoulol in Saccharomyces cerevisiae

“…This study primarily focused Unexpectedly, the knockout of the ROX1 gene and overexpression of the UPC2-1 gene led to a decrease in patchoulol production. Jordá et al [33] observed increased mRNA and protein levels of the ERG1 (squalene epoxygenase-encoding gene) gene after knocking down the ROX1 gene. We guessed that an enhancement in the metabolic pathway of epoxidized squalene may have competed with the patchoulol pathway for the precursor FPP, resulting in reduced patchoulol production.…”

Modes‐of‐action of antifungal compounds: Stressors and (target‐site‐specific) toxins, toxicants, or toxin–stressors

“…This has been demonstrated in S. cerevisiae , where iron deficiency increases the cell's susceptibility to terbinafine, a compound that inhibits squalene epoxidase Erg1 and so disrupts the ergosterol biosynthetic pathway. This has been attributed to both a decrease in Erg1 translation and the lanosterol‐induced degradation of Erg1 under iron deprivation conditions (Jordá et al, 2022 ).…”