Rational biosynthetic approaches for the production of new-to-nature compounds in fungi

• Published in: Fungal genetics and biology Vol. 89; pp. 89 - 101
• Main Authors: Boecker, Simon, Zobel, Sophia, Meyer, Vera, Süssmuth, Roderich D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2016
• Subjects: Aspergillus; Aspergillus - genetics; Aspergillus - metabolism; Biological Products; Combinatorial biosynthesis; Depsipeptides - isolation & purification; Drug Discovery - methods; Fungi - genetics; Fungi - metabolism; Metabolic engineering; Metabolic Engineering - methods; Mutasynthesis; Precursor-directed biosynthesis; Secondary metabolite; Combinatorial biosynthesis; Precursor-directed biosynthesis; Aspergillus; Metabolic engineering; Secondary metabolite; Mutasynthesis
• ISSN: 1087-1845; 1096-0937
• DOI: 10.1016/j.fgb.2016.02.003

[Display omitted] •Fungal secondary metabolites are a rich source for drug development.•Extension of fungal natural product portfolio by generation of non-natural compounds.•Description of past and recent strategies for fungal natural product diversification.•Covering examples from current state-of-the-art biosynthetic approaches.•Discussion of future challenges and perspectives. Filamentous fungi have the ability to produce a wide range of secondary metabolites some of which are potent toxins whereas others are exploited as food additives or drugs. Fungal natural products still play an important role in the discovery of new chemical entities for potential use as pharmaceuticals. However, in most cases they cannot be directly used as drugs due to toxic side effects or suboptimal pharmacokinetics. To improve drug-like properties, including bioactivity and stability or to produce better precursors for semi-synthetic routes, one needs to generate non-natural derivatives from known fungal secondary metabolites. In this minireview, we describe past and recent biosynthetic approaches for the diversification of fungal natural products, covering examples from precursor-directed biosynthesis, mutasynthesis, metabolic engineering and biocombinatorial synthesis. To illustrate the current state-of-the-art, challenges and pitfalls, we lay particular emphasis on the class of fungal cyclodepsipeptides which have been studied longtime for product diversification and which are of pharmaceutical relevance as drugs.