Kramer, Annemarie (2015) Fungal Biotechnology in Marine Natural Product Research. (PhD/ Doctoral thesis), Christian-Albrechts-Universität Kiel, Kiel, Germany, 123 pp.

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Abstract

The well recognized need of new chemical compounds for the development of drugs was recently again brought to the public ́s attention when the World Cancer Report was released in 2014. The translation of the immense bio- and chemodiversity of marine microorganisms into new drugs is one of the strengths of the marine biotechnology. The implementation of biotechnological production processes based on state-of-the-art technologies enables the sustainable use of marine resources. Recent advances in fungal biotechnology highlight the step towards the use of fungi as microbial cell factories. The marine fungus Microascus brevicaulis strain LF580 represents a non-model producer with high yields of the two cyclodepsipeptides scopularide A and B. The distinct activity of the two secondary metabolites against cancer cell lines put strain LF580 into the focus of the EU project MARINE FUNGI, which aimed the implementation of robust and sustainable biotechnological production processes of novel anticancer compounds. This thesis contributed to bridge gaps in the drug discovery pipeline of marine natural products: Methods were adapted and utilised in order to improve the production of the cyclodepsipeptides scopularide A and B. Comparative metabolomics revealed LF580 to be the best strain for further strain and process optimisation. The successful transfer to stirred tank reactor cultivation demonstrated marine natural products to be suitable for production using state-of-the-art bioprocess technologies. To avoid time-consuming genetic modification on strain level, a UV-mutant library was established (done by Linda Paun, CAU Kiel). The screening revealed a mutant strain with higher production, enhanced growth and a changed morphology. Comparative proteomics were applied in order to link molecular changes with physiological observations, providing an approximation towards a realistic description of the regulation of primary and secondary metabolism in LF580. The impact of physiology on the biotechnological process design was demonstrated by using this systematic approach. The integrated method design provided on the one hand fundamental knowledge on filamentous fungi and their biology, and on the other hand, enlarged the toolbox suitable for non-model fungal producer strains. Inter- and transdisciplinary approaches in the field of biotechnology help to provide a global view upon process design.

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