Abstract
Filamentous fungi represent an incredibly rich and rather overlooked reservoir of natural products, which often show potent bioactivity and find applications in different fields. Increasing the naturally low yields of bioactive metabolites within their host producers can be problematic, and yield improvement is further hampered by such fungi often being genetic intractable or having demanding culturing conditions. Additionally, total synthesis does not always represent a cost-effective approach for producing bioactive fungal-inspired metabolites, especially when pursuing assembly of compounds with complex chemistry. This review aims at providing insights into heterologous production of secondary metabolites from filamentous fungi, which has been established as a potent system for the biosynthesis of bioactive compounds. Numerous advantages are associated with this technique, such as the availability of tools that allow enhanced production yields and directing biosynthesis towards analogues of the naturally occurring metabolite. Furthermore, a choice of hosts is available for heterologous expression, going from model unicellular organisms to well-characterised filamentous fungi, which has also been shown to allow the study of biosynthesis of complex secondary metabolites. Looking to the future, fungi are likely to continue to play a substantial role as sources of new pharmaceuticals and agrochemicals—either as producers of novel natural products or indeed as platforms to generate new compounds through synthetic biology.
Highlights
Bioactive natural products from filamentous fungiFungi and other microorganisms represent an invaluable source of natural product (NP) bioactive compounds (Fig. 1), which are exploited in various contexts, ranging from crop protection to human medicine
Drug discovery has been greatly prompted by the increasing number of wholegenome sequences that have become available, which exposed a myriad of putative gene clusters for potentially bioactive compounds
Particular interest is given to antimicrobials, due to the reduction in effectiveness of existing antibiotics used to treat bacterial infections, which is seen as a major threat to global health security (Aiken et al 2014)
Summary
Fungi and other microorganisms represent an invaluable source of natural product (NP) bioactive compounds (Fig. 1), which are exploited in various contexts, ranging from crop protection to human medicine. The compounds that have been heterologously produced in E. coli are of bacterial origin In this context, a hallmark in heterologous production of complex nonribosomal peptide-polyketide hybrid (NRP-PK) natural products was established by Pfeifer et al (2003), who recreated complete biosynthesis of yersiniabactin (Ybt) in E. coli, upon heterologous expression of its gene cluster in a previously engineered strain of the model organism, which was able to support correct post-translational processing of the synthase enzyme (Pfeifer et al 2001). Further introduction of the remaining three genes of the gene cluster led to biosynthesis of the two final products aflatrem and β-aflatrem Another example of heterologous production of a fungal SM in A. oryzae was recently reported by Bailey et al (2016), who recreated total biosynthesis of the antibiotic pleuromutilin (23), a diterpene compound naturally produced by Clitopilus passeckerianus and related species (Hartley et al 2009). Total biosynthesis of these bioactive compounds through heterologous expression represents a far more appealing and inexpensive alternative
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