Discovery and Evaluation of Antimalarial, Anthelmintic, and Antimicrobial Marine Natural Products
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Sweeney-Jones, Anne Marie
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Abstract
Historically, natural products have served as valuable sources of drugs to treat many human diseases. Although many natural products are derived from terrestrial sources, the marine environment has the potential to provide a vast array of novel drug molecules since more than 70% of Earth’s surface is covered by relatively unexplored ocean habitats. An important aspect of the drug discovery process is evaluation of the mechanism of action (MOA) of bioactive molecules as this provides valuable information about the interaction of drug molecules with their target pathogen and allows for intelligent deployment of pharmaceuticals. Another relevant question to ask is what roles newly discovered marine natural products play in native environments since marine organisms do not encounter the same pathogens as humans in their own habitats. The work presented in this dissertation touches on all three of these research areas. The topic of drug discovery was explored through evaluation of extracts from marine organisms that exhibited either antimalarial or anthelmintic properties. This led to the identification of five antimalarial natural products, including the known compound lyngbyabellin A with promising nanomolar antimalarial activity and the novel molecule kakeromamide B, from a cyanobacterium Moorea producens. The MOA of kakeromamide B was evaluated using a computational approach to generate hypotheses about proteins that bind to the natural product, which were subsequently assessed experimentally. A metabolomics approach was used to investigate the MOA of a natural product isolated from the green alga Cladophora socialis against methicillin-resistant Staphylococcus aureus (MRSA). Preliminary experiments indicated that metabolomics successfully differentiated 1H NMR spectral data generated for MRSA treated with a range of antibiotics, however, further experiments are required to fully elucidate the MOA of cladophorol D. Evaluation of the ecological role of the natural product peyssonnoside A, isolated from a red alga Peyssonnelia sp., found that this natural product suppresses growth of a marine fungus, indicating an antifungal ecological role. In summary, this dissertation provides a comprehensive view of the many milestones involved in the natural product drug discovery process, from collection of marine organisms in the field to isolation and structural elucidation of bioactive natural products, and exploration of their biological functions. Important insights were gained by probing the ecological role of a natural product in its natural environment and evaluating possible MOAs of isolated natural products against human pathogens.
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2020-07-27
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Dissertation