Antifungal and Antileukemic Compounds from Cyanobacteria: Bioactivity, Biosynthesis, and Mechanism of Action

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Nature is a treasury of bioactive natural products that are developed into pharmaceuticals, cosmetics and other industrial applications. Natural products have an impact on all of us, for instance, in the form of antibiotics. Most of the drugs sold today are natural products or their derivatives. However, the need for new natural products has not decreased but is rather increasing. The incidences of certain diseases such as cancers are rising and resistance to treatment is a major problem. Especially prokaryotes and plants produce these intriguing natural products, which display several different bioactivities. Cyanobacteria are photosynthetic prokaryotes that belong to the most prolific sources of bioactive compounds. This study expands the knowledge of cyanobacterial natural products, including their activities, biosynthesis, and mechanisms of action. The University of Helsinki Cyanobacteria Culture Collection was utilized in this study. Cultured cyanobacteria were screened for antileukemic and antifungal activity using cell assays and disk diffusion analyses. Bioactive compounds were identified with spectrometric methods. The screenings revealed several bioactive hits, including antifungal, antileukemic and cytotoxic activities. Novel compound candidates and known compounds from new habitats or genera were found. In addition, novel variants of known compounds were identified. The results from screening were used to select cyanobacterial strains for whole genome sequencing. Genomic analysis was used to identify the biosynthesis gene clusters of the cytotoxic compounds swinholide and scytophycin. In addition, the production of swinholide was confirmed for the first time using axenic cyanobacteria. In the last part of the study, the mechanism of action of hassallidin was determined using cellular assays, imaging, and lipid models (in vitro and in silico). Hassallidin D purified from Anabaena sp. showed cholesterol-dependent lytic activity against eukaryotic cells. The development of a natural product into a drug or other application is a long process, but natural products are needed also in the future. This thesis contributes to this effort by increasing the understanding of several bioactive cyanobacterial natural compounds at both the functional and molecular level.

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