Doctor of Philosophy (Ph.D.)
Degree Granting Department
Bill J. Baker, Ph.D.
Juan Del Valle, Ph.D.
Lindsey Shaw, Ph.D.
X. Michael Shi, Ph.D.
Endophytic fungi, epigenetics, keikipukalide, bathyptilone, enbepenone, scotianone, Ntera-2, octocoral, Antarctica
Natural products are chemical compounds synthesized by a living organism. These compounds have been utilized by humans from ancient times to the present for their pharmacological and biological activities. Terrestrial organisms are considered a lucrative source of bioactive compounds and chemical diversity. Within the past 60 years, the marine environment has presented its potential as a validated source for structural diversity and biologically active compounds. Technology has given access from shallow waters down to the abyssal plane for exploration and investigation of the inhabitants. Marine organisms have displayed their benefits in the pharmaceutical industry with the approval of several marine-derived drugs active against various diseases.
This dissertation presents the potential of marine microbes, flora, and fauna specifically fungal endophytes, red alga and corals in drug discovery. Chapter 2 describes the isolation of secondary metabolites from endophytic fungi by manipulation of their epigenome. As a continuation of a screening project, prioritization of the extracts of the fungal endophytes was necessary for further chemical investigation based on the significant biological activity against two free-living amoebas; Naegleria fowleri and Acanthamoeba sp. Bioassay-guided isolation and mass-directed fractionation were the two methods utilized in the isolation of compounds — several known mycotoxins isolated with known biological activities against the amoeba. With repetition of isolating known compounds, mass-directed fractionation facilitated the pursuit of new compounds from bioactive extracts. A new compound was successfully isolated and is currently awaiting biological activity against N. fowleri. Chapter 3 demonstrates the ecological importance of secondary metabolites from the Antarctic red alga, Delisea pulchra. A suite of polyhalogenated polyketides was isolated and described. Five of the metabolites were previously described in the literature isolated from Delisea sp. and a new natural product isolated, previously reported as a synthetic precursor. The activity of these natural products as antibiotics is due to the structural similarities of a bacterial enzyme inhibitor. In Chapter 4, Antarctic corals collected from depths starting deeper than 800 m. The first coral described, afforded seven new and known diterpenes in which their structure elucidation is detailed. Varying biological activity against the parasite Leishmania donovani was found from these furanocembranes. Another suite of diterpenes was isolated from a second Antarctic coral Anthoptilum sp. These compounds are structurally related to briarane diterpenes with modifications leading to three new compounds. The fourth compound isolated presented a newly reported scaffold. These compounds tested against several biological targets; discovering one of the diterpenes significantly active against an induced neuronal cell assay called Ntera-2. A third coral was chemically investigated producing two halogenated sesquiterpenes. The structures were elucidated using one- and two- dimensional NMR analysis, HRESIMS, and x-ray crystallography. This scaffold is common in terrestrial sources as well as another marine source. These compounds were tested against various disease targets in which one of the compounds were discovered to be moderately active against the bacterium Mycobacterium tuberculosis. This dissertation demonstrates the pharmaceutical potential of natural products from marine organisms.
Scholar Commons Citation
Thomas, Santana Alexa Lavonia, "The Potential of Marine Microbes, Flora and Fauna in Drug Discovery" (2019). Graduate Theses and Dissertations.