New molecular methods for global activation of cryptic biosynthetic gene clusters

"Actinobacterial Natural Products are an important source of commercially used compounds, including many clinically used antibiotic, antifungal and anticancer compounds. The genes required to produce these compounds are encoded by Biosynthetic Gene Clusters (BGCs). Genomic sequence data have revealed the presence of a large fraction of putatively silent biosynthetic gene clusters in the genomes of actinomycetes that encode for secondary metabolites, which are not detected under standard fermentation conditions.

We have developed a system that can boost the weak production from these clusters and has application for the discovery of new antibiotics and antifungal compounds. This project will allow the methods to be optimised and applied to other BGCs of known or unknown function. In addition we will further develop this method and combine the system with a transposon which can then be inserted randomly into the genomes of actinomycetes boosting the production of natural products in this area. The system has application for boosting compound titre from known BGCs and will be used for the identification of otherwise undetectable antibiotic and antifungal compounds. The system will be used on a variety of rare actinomycetes and induced novel antibiotic and antifungal compounds will be characterised."