Global Genome Mining for Unexploited Bioactive Natural Products in Filamentous Fungi
DescriptionOne of the key features of natural products, organic compounds produced by living organisms, is their broad range of biological activities, making natural products rich and attractive sources for drug development. However, as a significant number of natural products have been isolated and characterized over the past decades, we now need innovative approaches to continue efficiently discovering new bioactive natural products. Intriguingly, some biosynthetic gene clusters of bioactive microbial natural products encode a self-resistance enzyme, which is a closely homologous but resistant version of the enzyme inhibited by the toxic natural product. In recent years, the advance in genome sequencing technology has led to the accumulation of a large number of microbial genome sequences, which has revealed the presence of many unexploited biosynthetic gene clusters. Thus, the identification and characterization of cryptic biosynthetic gene clusters that potentially harbor a self-resistance enzyme gene would afford natural products with a predictable biological activity. This proposed project will therefore seek to (i) perform a global search of biosynthetic gene clusters that potentially encode a self-resistance enzyme in filamentous fungi, (ii) obtain a series of bioactive molecules by characterizing the identified gene clusters, and (iii) evaluate their biological activities to provide future drug leads.To achieve the goals described above, the applicant has developed an algorithm that automatically extracts gene clusters with a possible self-resistance enzyme gene from a given fungal genome sequence. Furthermore, an improved method for fungal transformation is being developed by the applicant’s group, which could allow for the rapid and efficient heterologous expression of virtually any fungal biosynthetic gene cluster. In this proposed project, publicly available fungal genomes will first be analyzed by the algorithm, which will provide a number of biosynthetic gene clusters with potentially bioactive molecules. Selected gene clusters will be heterologously expressed in the fungus Aspergillus oryzae. If the transformant yields a new metabolite, it will be isolated and characterized by spectroscopic analyses. The biological activity of the obtained natural products, such as antifungal activity, will then be investigated, and the molecular target of the bioactive compounds will be validated. For a few selected compounds with potent activity, the biosynthetic pathway will also be elucidated.In summary, this project will discover several biologically active natural products in an efficient manner. Some of the obtained molecules might have a potent biological activity and could thus serve as a lead compound for future drug development.
|Effective start/end date||1/01/23 → …|