Graduate Thesis Or Dissertation
 

Drug Discovery and Chemical Ecology Investigations of Specialized Metabolism in Tolypocladium and Paraisaria

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  • Since the discovery of penicillin in 1928, the fungal kingdom has remained a fertile source for the discovery of new, biologically active, natural products. Further, as natural products continue to be discovered from fungi, a deeper understanding of the critical role of specialized metabolism in fungal ecology is afforded. The research presented here focuses on insect-pathogenic fungi in two genera in family Ophiocordycipitaceae (Hypocreales, Ascomycota): Tolypocladium, and Paraisaria. Traditional drug discovery methods were used toward the isolation and structure elucidation of new biologically active natural products. In addition, metabolomics informed by bioinformatics was employed to unify the products of biosynthetic families, and to investigate the evolution and ecological functions of peptidic natural products. These investigations resulted in the discovery of new, eleven residue linear lipopeptides, tolypocladamides, possessing the unique amino acid 4-[(E)-2-butenyl]-4-methyl-L-threonine (Bmt), a proposed core biosynthetic gene, and the comprehensive structure determination of tolypocladamide H, from the beetle pathogen, Tolypocladium inflatum. Investigations of the fungal genus, Paraisaria led to the discovery of a family of cytotoxic N-methylated seven-residue cyclic peptides, named tortuosins, from the new beetle pathogen, P. tortuosa. Metabolomics analyses revealed that the tortuosin molecular family is widely produced in genus Paraisaria. A novel application of molecular cartography to study a host-pathogen system, revealed that tortuosins likely function as virulence factors. Lastly, the possible role of tortuosins as mycotoxins affecting human health is suggested for further investigation.
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  • Ongoing Research
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  • 2022-06-09 to 2023-07-10

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