One of the exciting movements in microbial sciences has been a refocusing and revitalization of efforts to mine the fungal secondary metabolome. The magnitude of biosynthetic gene clusters (BGCs) in ...a single filamentous fungal genome combined with the historic number of sequenced genomes suggests that the secondary metabolite wealth of filamentous fungi is largely untapped. Mining algorithms and scalable expression platforms have greatly expanded access to the chemical repertoire of fungal-derived secondary metabolites. In this Review, I discuss new insights into the transcriptional and epigenetic regulation of BGCs and the ecological roles of fungal secondary metabolites in warfare, defence and development. I also explore avenues for the identification of new fungal metabolites and the challenges in harvesting fungal-derived secondary metabolites.
Filamentous fungi are renowned for the production of a diverse array of secondary metabolites (SMs) where the genetic material required for synthesis of a SM is typically arrayed in a biosynthetic ...gene cluster (BGC). These natural products are valued for their bioactive properties stemming from their functions in fungal biology, key among those protection from abiotic and biotic stress and establishment of a secure niche. The producing fungus must not only avoid self-harm from endogenous SMs but also deliver specific SMs at the right time to the right tissue requiring biochemical aid. This review highlights functions of BGCs beyond the enzymatic assembly of SMs, considering the timing and location of SM production and other proteins in the clusters that control SM activity. Specifically, self-protection is provided by both BGC-encoded mechanisms and non-BGC subcellular containment of toxic SM precursors; delivery and timing is orchestrated through cellular trafficking patterns and stress- and developmental-responsive transcriptional programs.
About the Authors: Nicholas Raffa Affiliation: Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America ORCID logo ...http://orcid.org/0000-0003-0112-5262 Nancy P. Keller * E-mail: npkeller@wisc.edu Affiliations Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America, Department of Bacteriology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America ORCID logo http://orcid.org/0000-0002-4386-9473 Introduction Aspergillus fumigatus is a ubiquitous saprophytic mold able to grow on a diversity of material ranging from decayed organic matter in the environment to space station cupolas 1. The compound displays activity against Toxoplasma gondii and Trypanosoma cruzi in vitro that causes toxoplasmosis and Chagas disease, respectively. Helvolic acid Helvolic acid is a fusidane antibiotic that exhibits in vitro antiprotozoal activity against the trypanosome Trypanosoma brucei brucei GUTat3.1, the causative agent of African sleeping sickness 29, and helvolic acid derivatives exhibit antibacterial activity against Streptococcus agalactiae and Staphylococcus aureus 30. Macheleidt J, Scherlach K, Neuwirth T, Schmidt‐Heck W, Straßburger M, Spraker J, Baccile JA, Schroeder FC, Keller NP, Hertweck C, Heinekamp T. Transcriptome analysis of cyclic AMP‐dependent protein kinase A–regulated genes reveals the production of the novel natural compound fumipyrrole by Aspergillus fumigatus.
Fungi produce an abundance of bioactive secondary metabolites which can be utilized as antibiotics and pharmaceutical drugs. The genes encoding secondary metabolites are contiguously arranged in ...biosynthetic gene clusters (BGCs), which supports co-regulation of all genes required for any one metabolite. However, an ongoing challenge to harvest this fungal wealth is the finding that many of the BGCs are ‘silent’ in laboratory settings and lie in heterochromatic regions of the genome. Successful approaches allowing access to these regions - in essence converting the heterochromatin covering BGCs to euchromatin - include use of epigenetic stimulants and genetic manipulation of histone modifying proteins. This review provides a comprehensive look at the chromatin remodeling proteins which have been shown to regulate secondary metabolism, the use of chemical inhibitors used to induce BGCs, and provides future perspectives on expansion of epigenetic tools and concepts to mine the fungal metabolome.
An important goal of the mycotoxin research community is to develop comprehensive strategies for mycotoxin control and detoxification. Although significant progress has been made in devising such ...strategies, yet, there are barriers to overcome and gaps to fill in order to design effective mycotoxin management techniques. This is in part due to a lack of understanding of why fungi produce these toxic metabolites. Here we present cumulative evidence from the literature that indicates an important ecological role for mycotoxins, with particular focus on
mycotoxins. Further, we suggest that understanding how mycotoxin levels are regulated by microbial encounters can offer novel insights for mycotoxin control in food and feed. Microbial degradation of mycotoxins provides a wealth of chemical information that can be harnessed for large-scale mycotoxin detoxification efforts.
Aspergillus flavus Amaike, Saori; Keller, Nancy P
Annual review of phytopathology,
01/2011, Letnik:
49
Journal Article
Recenzirano
Aspergillus flavus is saprophytic soil fungus that infects and contaminates preharvest and postharvest seed crops with the carcinogenic secondary metabolite aflatoxin. The fungus is also an ...opportunistic animal and human pathogen causing aspergillosis diseases with incidence increasing in the immunocompromised population. Whole genome sequences of A. flavus have been released and reveal 55 secondary metabolite clusters that are regulated by different environmental regimes and the global secondary metabolite regulators LaeA and VeA. Characteristics of A. flavus associated with pathogenicity and niche specialization include secondary metabolite production, enzyme elaboration, and a sophisticated oxylipin host crosstalk associated with a quorum-like development program. One of the more promising strategies in field control involves the use of atoxic strains of A. flavus in competitive exclusion studies. In this review, we discuss A. flavus as an agricultural and medical threat and summarize recent research advances in genomics, elucidation of parameters of pathogenicity, and control measures.
Filamentous fungi produce a diverse array of secondary metabolites (SMs) critical for defense, virulence, and communication. The metabolic pathways that produce SMs are found in contiguous gene ...clusters in fungal genomes, an atypical arrangement for metabolic pathways in other eukaryotes. Comparative studies of filamentous fungal species have shown that SM gene clusters are often either highly divergent or uniquely present in one or a handful of species, hampering efforts to determine the genetic basis and evolutionary drivers of SM gene cluster divergence. Here, we examined SM variation in 66 cosmopolitan strains of a single species, the opportunistic human pathogen Aspergillus fumigatus. Investigation of genome-wide within-species variation revealed 5 general types of variation in SM gene clusters: nonfunctional gene polymorphisms; gene gain and loss polymorphisms; whole cluster gain and loss polymorphisms; allelic polymorphisms, in which different alleles corresponded to distinct, nonhomologous clusters; and location polymorphisms, in which a cluster was found to differ in its genomic location across strains. These polymorphisms affect the function of representative A. fumigatus SM gene clusters, such as those involved in the production of gliotoxin, fumigaclavine, and helvolic acid as well as the function of clusters with undefined products. In addition to enabling the identification of polymorphisms, the detection of which requires extensive genome-wide synteny conservation (e.g., mobile gene clusters and nonhomologous cluster alleles), our approach also implicated multiple underlying genetic drivers, including point mutations, recombination, and genomic deletion and insertion events as well as horizontal gene transfer from distant fungi. Finally, most of the variants that we uncover within A. fumigatus have been previously hypothesized to contribute to SM gene cluster diversity across entire fungal classes and phyla. We suggest that the drivers of genetic diversity operating within a fungal species shown here are sufficient to explain SM cluster macroevolutionary patterns.
Strategies for mining fungal natural products Wiemann, Philipp; Keller, Nancy P
Journal of industrial microbiology & biotechnology,
02/2014, Letnik:
41, Številka:
2
Journal Article
Recenzirano
Fungi are well known for their ability to produce a multitude of natural products. On the one hand their potential to provide beneficial antibiotics and immunosuppressants has been maximized by the ...pharmaceutical industry to service the market with cost-efficient drugs. On the other hand identification of trace amounts of known mycotoxins in food and feed samples is of major importance to ensure consumer health and safety. Although several fungal natural products, their biosynthesis and regulation are known today, recent genome sequences of hundreds of fungal species illustrate that the secondary metabolite potential of fungi has been substantially underestimated. Since expression of genes and subsequent production of the encoded metabolites are frequently cryptic or silent under standard laboratory conditions, strategies for activating these hidden new compounds are essential. This review will cover the latest advances in fungal genome mining undertaken to unlock novel products.
Hyphal growth is essential for host colonization during Aspergillus infection. The transcription factor ZfpA regulates A. fumigatus hyphal development including branching, septation, and cell wall ...composition. However, how ZfpA affects fungal growth and susceptibility to host immunity during infection has not been investigated. Here, we use the larval zebrafish-Aspergillus infection model and primary human neutrophils to probe how ZfpA affects A. fumigatus pathogenesis and response to antifungal drugs in vivo. ZfpA deletion promotes fungal clearance and attenuates virulence in wild-type hosts and this virulence defect is abrogated in neutrophil-deficient zebrafish. ZfpA deletion also increases susceptibility to human neutrophils ex vivo while overexpression impairs fungal killing. Overexpression of ZfpA confers protection against the antifungal caspofungin by increasing chitin synthesis during hyphal development, while ZfpA deletion reduces cell wall chitin and increases caspofungin susceptibility in neutrophil-deficient zebrafish. These findings suggest a protective role for ZfpA activity in resistance to the innate immune response and antifungal treatment during A. fumigatus infection.
Summary
Microorganisms reside in diverse environmental communities where interactions become indispensable due to close physical associations. These interactions are driven by chemical communication ...among different microbial kingdoms, particularly between fungi and bacteria. Knowledge about these communication signals provides useful information about the nature of microbial interactions and allows predictions of community development in diverse environments. Here, we provide an update on the role of small signalling molecules in fungal–bacterial interactions with focus on agricultural and medicinal environments. This review highlights the range of – and response to – diverse biochemicals produced by both kingdoms with view to harnessing their properties towards drug discovery applications.
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