Fungal penicillin has saved the lives of millions since its discovery by Fleming in the 1920s. However, antimicrobial resistance is currently spreading, whereas the number of newly discovered antibiotics is declining.  The World Health Organization forecasts a disaster due to the dramatic increase in antimicrobial resistance all over the world underlining an urgent need for novel drugs. The European Centre for Disease Prevention and Control (ECDC) estimated that each year 25’000 Europeans die as a direct consequence of multidrug-resistant infection with an economic impact of an estimated € 1.5 billion per year (Dr. M. Springer, ECDC Director, European press room, Brussels, 17 November 2011).

The need to identify novel bioactive fungal products goes far beyond antibiotics and includes the requirement for novel drugs for multiple human health problems ranging from different cancers to increasing neurodegenerative diseases, which are especially prominent in aging societies. Bioactive compounds produced by filamentous fungi and important for human welfare are, for example, cyclosporine A (immunosuppressive agent), lovastatin (cholesterol-lowering agent), taxol (anticancer agent) and griseofulvin (antifungal agent). Another important aspect is that fungi are destructive pathogens of plants and responsible for enormous crop losses worldwide. More than 10% of the annual harvested crops are estimated to be spoiled by fungi.

 

The fungal kingdom of approximately 1.5 million species exhibits a huge reservoir of potent chemicals as secondary metabolites that span a broad field of structurally and chemically diverse natural products. This reservoir has a considerable potential impact on human life for both disease treatment and food spoilage. The genomes of filamentous fungi comprise an untapped resource of numerous putative genes and gene clusters for diverse secondary metabolites (SM) which are not normally expressed under laboratory conditions. The key aim of this project is to find novel bioactive molecules by exploiting the wealth of fungal biodiversity and to translate these into useful products.

Overall, a programme of training has been devised encompassing the main skill sets required in the product development pipeline from discovery to production, scale-up and commercial manufacture and will broaden the knowledge of all trainees. The focus of this proposal is:

(i) to train a new generation of problem-solving oriented, creative European scientists. Advanced research on fungal SM biosynthesis and production requires a multi-scale view – i.e. the combination of knowledge on cellular and molecular biology with biophysical modelling, statistical / computational tools and industrial production – and hence a high level of expertise in these disciplines.

(ii) to explore the potential of model fungal strains for the production of novel secondary metabolites. This requires synthetic biology, ‘omics’ level analysis, network analysis and modelling. The distribution of uncharacterized putative SM clusters among the available fungal genomes will be compared and characterized to identify novel enzyme activities as well as novel secondary metabolite molecules. The final aim is to set the stage for rationally designed SM-overproducing and/or SM-free strains for use in industrial biotechnology.

(iii) to explore novel fungi isolated from the environment. The majority of the fungal kingdom can each produce hundreds of different secondary chemicals including bioactive compounds ranging from putative drugs to deleterious mycotoxins. The potency of the fungal natural products makes them attractive in order to exploit them not only against pathogenic microorganisms as anti-bacterial, -viral, -fungal, or -protozoan agents but also to explore their influence against cancer cells or for treatment of other diseases. Interesting fungal clusters discovered in novel fungal genomes from a variety of environments (available through culture collections held by network partners) will be transferred to established fungal cell factories as well as to tailored fungal producers lacking other secondary metabolite clusters to overexpress secondary metabolite genes, isolate and characterize the compound and finally test their bioactive potential.