Journal Article

Environmental fungi target thiol homeostasis to compete with Mycobacterium tuberculosis

Barry, Clifton Earl, Andrews, Jenna, Malhotra, Neha, Markowitz, Tovah E., Lack, Justin, Goodwin, Michael, Oh, Sangmi, Finin, Peter, Medrano, Jessica, Boshoff, Helena I. M.

2024

Overview

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 Mycobacterium tuberculosis ( Mtb ) to look for inducible expression of antitubercular agents and identified 5 fungi that produced cidal antitubercular agents upon exposure to live Mtb . Whole genome sequencing of these fungi followed by fungal RNAseq after Mtb 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 3 of these potent electrophiles react with thiols and treatment of Mtb cells with these agents followed by Mtb RNAseq showed that these natural products all induce profound thiol stress suggesting a rapid depletion of mycothiol. The induction of thiol-reactive mycotoxins through 3 different systems in response to exposure to Mtb suggests that fungi have identified this as a highly vulnerable target in a similar microenvironment to that of the caseous human lesion.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Antitubercular agents / Antitubercular Agents - pharmacology / Bacteria / Biology and Life Sciences / Bogs / Cell culture / Citrinin / Citrinin - metabolism / Coculture Techniques / Competition / Competition (Biology) / Culture / Earth Sciences / Ecology and Environmental Sciences / Environmental aspects / Exposure / Fungi / Fungi - genetics / Fungi - metabolism / Fungi - pathogenicity / Gene clusters / Gene expression / Gene Expression Regulation, Fungal / Gene sequencing / Granulomas / Homeostasis / Laboratories / Leprosy / Microbiological research / Microenvironments / Microorganisms / Multigene Family / Mycobacterium tuberculosis / Mycobacterium tuberculosis - genetics / Mycobacterium tuberculosis - metabolism / Mycothiol / Mycotoxins / Mycotoxins - metabolism / Natural products / Nutrients / Patulin / Peat / Peat bogs / Physical Sciences / Physiological aspects / Research and analysis methods / Sulfhydryl Compounds - metabolism / Thiols / Tuberculosis / Whole genome sequencing / Wildlife sanctuaries