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      Targeted induction of a silent fungal gene cluster encoding the bacteria-specific germination inhibitor fumigermin

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          Abstract

          Microorganisms produce numerous secondary metabolites (SMs) with various biological activities. Many of their encoding gene clusters are silent under standard laboratory conditions because for their activation they need the ecological context, such as the presence of other microorganisms. The true ecological function of most SMs remains obscure, but understanding of both the activation of silent gene clusters and the ecological function of the produced compounds is of importance to reveal functional interactions in microbiomes. Here, we report the identification of an as-yet uncharacterized silent gene cluster of the fungus Aspergillus fumigatus, which is activated by the bacterium Streptomyces rapamycinicus during the bacterial-fungal interaction. The resulting natural product is the novel fungal metabolite fumigermin, the biosynthesis of which requires the polyketide synthase FgnA. Fumigermin inhibits germination of spores of the inducing S. rapamycinicus, and thus helps the fungus to defend resources in the shared habitat against a bacterial competitor.

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          Fungal secondary metabolism - from biochemistry to genomics.

          Much of natural product chemistry concerns a group of compounds known as secondary metabolites. These low-molecular-weight metabolites often have potent physiological activities. Digitalis, morphine and quinine are plant secondary metabolites, whereas penicillin, cephalosporin, ergotrate and the statins are equally well known fungal secondary metabolites. Although chemically diverse, all secondary metabolites are produced by a few common biosynthetic pathways, often in conjunction with morphological development. Recent advances in molecular biology, bioinformatics and comparative genomics have revealed that the genes encoding specific fungal secondary metabolites are clustered and often located near telomeres. In this review, we address some important questions, including which evolutionary pressures led to gene clustering, why closely related species produce different profiles of secondary metabolites, and whether fungal genomics will accelerate the discovery of new pharmacologically active natural products.
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            Regulation of fungal secondary metabolism.

            Fungi produce a multitude of low-molecular-mass compounds known as secondary metabolites, which have roles in a range of cellular processes such as transcription, development and intercellular communication. In addition, many of these compounds now have important applications, for instance, as antibiotics or immunosuppressants. Genome mining efforts indicate that the capability of fungi to produce secondary metabolites has been substantially underestimated because many of the fungal secondary metabolite biosynthesis gene clusters are silent under standard cultivation conditions. In this Review, I describe our current understanding of the regulatory elements that modulate the transcription of genes involved in secondary metabolism. I also discuss how an improved knowledge of these regulatory elements will ultimately lead to a better understanding of the physiological and ecological functions of these important compounds and will pave the way for a novel avenue to drug discovery through targeted activation of silent gene clusters.
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              Discovery of microbial natural products by activation of silent biosynthetic gene clusters.

              Microorganisms produce a wealth of structurally diverse specialized metabolites with a remarkable range of biological activities and a wide variety of applications in medicine and agriculture, such as the treatment of infectious diseases and cancer, and the prevention of crop damage. Genomics has revealed that many microorganisms have far greater potential to produce specialized metabolites than was thought from classic bioactivity screens; however, realizing this potential has been hampered by the fact that many specialized metabolite biosynthetic gene clusters (BGCs) are not expressed in laboratory cultures. In this Review, we discuss the strategies that have been developed in bacteria and fungi to identify and induce the expression of such silent BGCs, and we briefly summarize methods for the isolation and structural characterization of their metabolic products.
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                Author and article information

                Contributors
                Role: Reviewing Editor
                Role: Senior Editor
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                21 February 2020
                2020
                : 9
                : e52541
                Affiliations
                [1 ]Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology (HKI) JenaGermany
                [2 ]Institute of Microbiology, Friedrich Schiller University Jena JenaGermany
                [3 ]Department of Biomolecular Chemistry, HKI JenaGermany
                [4 ]Leibniz Research Group – Biobricks of Microbial Natural Product Syntheses, HKI JenaGermany
                Harvard Medical School United States
                National Institute of Child Health and Human Development United States
                Harvard Medical School United States
                Harvard Medical School United States
                UCLA United States
                Author notes
                [†]

                Department of Biology, McMaster University, Hamilton, Canada.

                Author information
                https://orcid.org/0000-0003-4049-1062
                http://orcid.org/0000-0003-4845-9366
                http://orcid.org/0000-0002-4405-169X
                https://orcid.org/0000-0002-8814-4193
                Article
                52541
                10.7554/eLife.52541
                7034978
                32083553
                2787a8ef-1933-435d-b511-a46bf551fabf
                © 2020, Stroe et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 07 October 2019
                : 09 February 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award ID: Collaborative Research Center 1127 ChemBioSys (projects B01)
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award ID: Collaborative Research Center 1127 ChemBioSys (projects B02)
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100002347, Bundesministerium für Bildung und Forschung;
                Award ID: DrugBioTune
                Award Recipient :
                Funded by: International Leibniz Research School;
                Award ID: Microbial and Biomolecular Interactions
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Research Article
                Ecology
                Microbiology and Infectious Disease
                Custom metadata
                A silent gene cluster of the fungus Aspergillus fumigatus is activated by a bacterium and leads to the production of a novel spore germination inhibitor targeting the inducing bacterium.

                Life sciences
                aspergillus fumigatus,streptomyces rapamycinicus,secondary metabolism,germination inhibition,microbial interaction,polyketide,other

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