Modulation of yeast Erg1 expression and terbinafine susceptibility by iron bioavailability

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 strain-specific 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.This research was supported by grant PID2020-116940RB-I00 funded by MCIN/AEI/ 10.13039/501100011033 and predoctoral fellowship ACIF/2019/214 funded by ‘Generalitat Valenciana’. We also acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI).Peer reviewe