Silber, Johanna (2014) Characterization of new natural products from fungi of the German Wadden Sea. (PhD/ Doctoral thesis), Christian-Albrechts-Universität Kiel, Kiel, Germany, 115 pp.

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Abstract

Fungi are prolific producers of natural products used for pharmaceutical and agricultural applications. The scope of the present PhD study was to exploit this extraordinary biosynthetic potential for the search for new natural products from fungal isolates of the German Wadden Sea. In order to create a smart screening strategy, four criteria were applied to select fungi for subsequent thorough investigation with regard to their natural product biosynthetic abilities: (i) fungal isolates from a little-explored ecosystem, (ii) less studied genera, (iii) genetic potential according to polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) gene sequences, (iv) stimulating effects on biosynthesis by variation of culture conditions. The screening strategy was proven effective as it led to the discovery of nine new natural products, namely, calcaripeptides A–C, calcarides A–E and one tropolone derivative. The calcaripeptides are cyclodepsipeptides that were isolated from a Calcarisporium sp. (strain KF525). The structure elucidation employing one- and two-dimensional nuclear magnetic resonance (NMR) spectroscopy techniques proved the compounds to possess an unusual macrocycle composed of two amino acids and a nonpeptidic substructure. The absolute configuration of the calcaripeptides was determined by X-ray crystallography in combination with the advanced Marfey’s method. Biosynthetic studies on calcaripeptide A showed that the nonpeptidic structural part of the compound originated from acetate and L-methionine, suggesting a biosynthetic origin from a PKS–
NRPS hybrid. Despite broad testing for biological activities, the calcaripeptides did not exhibit any inhibitory properties. In addition, strain KF525 produced a second structural class of natural products including the new calcarides A–E and five related compounds of the 15G256-type. The compounds are linear and macrocyclic polyesters with the calcarides representing methylated forms of the 15G256-type compounds. The absolute configuration of the metabolites was investigated by measurements of the optical rotation. The calcarides and 15G256-type compounds were found to possess antibacterial activities against Staphylococcus epidermidis, Xanthomonas campestris and Propionibacterium acnes underlying tight structure-activity relationships. From another fungal strain, Cladosporium sp. KF501, members of the family of tropolone fungal metabolites were isolated. Among the compounds was a new derivative that represents a stereoisomer of the known tropolones of the strain. Single-crystal X-ray diffraction analysis was employed in order to determine the relative configuration of the new derivative. The isolated tropolones showed antibacterial and antifungal properties when profiled against Xanthomonas campestris and Trichophyton rubrum. Overall, the results of the study demonstrate the high value of fungi from marine habitats for the discovery of new bioactive natural products.

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