EneA of Aspergillus fumigatus is a regulator of secondary metabolism and enhances nscA expression in presence of polyenes and Streptomyces

Aspergillus fumigatus is a soil born fungus, which can induce severe aspergillosis in immunocompromised patients. In this study, we investigated the zinc cluster transcription factor EneA (enhancer of nscA expression A) of A. fumigatus, which is required for adaption to polyenes and for competition with soil living streptomycetes. In presence of polyenes, the polyketidesynthase encoding gene nscA, which is part of the neosartoricin/fumicycline gene cluster, is induced in dependency of EneA via NscR. In contrast, high levels of eneA transcripts lead to increased nscA expression in the absence of nscR, suggesting differing regulatory pathways for neosartoricin production depending on EneA. Moreover, overexpression of eneA leads to the induction of genes from nine different secondary metabolite clusters, comprising several of which are known to produce toxins, revealing EneA as a global regulator of secondary metabolism. We demonstrate that these metabolites reduce amphotericin B toxicity and inhibit the growth of streptomycetes. Finally, we show that polyenes and metabolites derived from Streptomycetes noursei promote increased neosartoricin production via EneA. These findings suggest that the EneA-dependent adaptation of A. fumigatus in its natural habitat may contribute to enhanced tolerance to antifungal agents, such as amphotericin B, and augmented resistance to the host’s immune defenses.