Environmental sphagnum-associated fungi target thiol homeostasis to compete with .

Mycobacterial species in nature are found in abundance in sphagnum peat bogs where they compete for nutrients with a variety of microorganisms including fungi. We screened a collection of fungi isolated from sphagnum bogs by co-culture with () to look for inducible expression of antitubercular agents and identified five fungi that produced cidal antitubercular agents upon exposure to live . Whole genome sequencing of these fungi followed by fungal RNAseq after exposure allowed us to identify biosynthetic gene clusters induced by co-culture. Three of these fungi induced expression of patulin, one induced citrinin expression and one induced the production of nidulalin A. The biosynthetic gene clusters for patulin and citrinin have been previously described but the genes involved in nidulalin A production have not been described before. All three of these potent electrophiles react with thiols and treatment of cells with these agents followed by RNAseq showed that these natural products all induce profound thiol stress suggesting a rapid depletion of mycothiol. The induction of thiol-reactive mycotoxins through three different systems in response to exposure to suggests that fungi have identified this as a highly vulnerable target in a similar microenvironment to that of the caseous human lesion.