Publikationen

An unusual polyketide with a new carbon skeleton, lindgomycin (1), and the recently described ascosetin (2) were extracted from mycelia and culture broth of different Lindgomycetaceae strains, which were isolated from a sponge of the Kiel Fjord in the Baltic Sea (Germany) and from the Antarctic. Their structures were established by spectroscopic means. In the new polyketide, two distinct domains, a bicyclic hydrocarbon and a tetramic acid, are connected by a bridging carbonyl. The tetramic acid substructure of compound 1 was proved to possess a unique 5-benzylpyrrolidine-2,4-dione unit. The combination of 5-benzylpyrrolidine-2,4-dione of compound 1 in its tetramic acid half and 3-methylbut-3-enoic acid pendant in its decalin half allow the assignment of a new carbon skeleton. The new compound 1 and ascosetin showed antibiotic activities with IC50 value of 5.1 ($\pm$0.2) ?M and 3.2 ($\pm$0.4) \ensuremath\muM, respectively, against methicillin-resistant Staphylococcus aureus.

This study covers the isolation, testing, and identification of natural products with anticancer properties. Secondary metabolites were isolated from fungal strains originating from a variety of marine habitats. Strain culture protocols were optimized with respect to growth media composition and fermentation conditions. From these producers, isolated compounds were screened for their effect on the viability and proliferation of a subset of the NCI60 panel of cancer cell lines. Active compounds of interest were identified and selected for detailed assessments and structural elucidation using nuclear magnetic resonance. This revealed the majority of fungal-derived compounds represented known anticancer chemotypes, confirming the integrity of the process and the ability to identify suitable compounds. Examination of effects of selected compounds on cancer-associated cell signaling pathways used phospho flow cytometry in combination with 3D fluorescent cell barcoding. In parallel, the study addressed the logistical aspects of maintaining multiple cancer cell lines in culture simultaneously. A potential solution involving microbead-based cell culture was investigated (BioLevitator, Hamilton). Selected cell lines were cultured in microbead and 2D methods and cell viability tests showed comparable compound inhibition in both methods (R-2=0.95). In a further technology assessment, an image-based assay system was investigated for its utility as a possible complement to ATP-based detection for quantifying cell growth and viability in a label-free manner.

The biological resources of the oceans have been exploited since ancient human history, mainly by catching fish and harvesting algae. Research on natural products with special emphasis on marine animals and also algae during the last decades of the 20th century has revealed the importance of marine organisms as producers of substances useful for the treatment of human diseases. Though a large number of bioactive substances have been identified, some many years ago, only recently the first drugs from the oceans were approved. Quite astonishingly, the immense diversity of microbes in the marine environments and their almost untouched capacity to produce natural products and therefore the importance of microbes for marine biotechnology was realized on a broad basis by the scientific communities only recently. This has strengthened worldwide research activities dealing with the exploration of marine microorganisms for biotechnological applications, which comprise the production of bioactive compounds for pharmaceutical use, as well as the development of other valuable products, such as enzymes, nutraceuticals and cosmetics. While the focus in these fields was mainly on marine bacteria, also marine fungi now receive growing attention. Although culture-dependent studies continue to provide interesting new chemical structures with biological activities at a high rate and represent highly promising approaches for the search of new drugs, exploration and use of genomic and metagenomic resources are considered to further increase this potential. Many efforts are made for the sustainable exploration of marine microbial resources. Large culture collections specifically of marine bacteria and marine fungi are available. Compound libraries of marine natural products, even of highly purified substances, were established. The expectations into the commercial exploitation of marine microbial resources has given rise to numerous institutions worldwide, basic research facilities as well as companies. In Europe, recent activities have initiated a dynamic development in marine biotechnology, though concentrated efforts on marine natural product research are rare. One of these activities is represented by the Kieler Wirkstoff-Zentrum KiWiZ, which was founded in 2005 in Kiel (Germany).