Iron deficiency and the fungal protein Dde1 contribute to azole susceptibility in Saccharomyces cerevisiae and Candida glabrata.

Abstract

The increasing incidence of opportunistic fungal infections has led to the widespread utilization of azoles, which target lanosterol 14α-demethylase (Erg11), a heme-dependent enzyme essential for ergosterol biosynthesis. Previous studies identified the conserved Dap1 protein as a regulator of Erg11 function. In this study, we investigated Dde1, a fungal protein that physically interacts with Dap1. Deletion of DDE1 in both Saccharomyces cerevisiae and Candida glabrata resulted in increased sensitivity to azoles and iron depletion, together with alterations in sterol composition consistent with impaired Erg11 activity. Checkerboard assays further revealed a synergistic interaction between iron chelation and fluconazole not only in C. glabrata but also in laboratory and virulent isolates of S. cerevisiae. In addition, gene expression analyses showed that iron limitation attenuates the induction of ERG11 and DDE1 in response to azole treatment. Notably, synergism between iron chelation and fluconazole was retained, although at lower antifungal concentrations, in dap1Δ and dde1Δ mutants, indicating that additional factors contribute to this interaction. Although clinical validation is still required, these findings highlight the therapeutic potential of combining azoles with iron chelation and support Dde1 as a promising fungal-specific target for antifungal drug development.

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