Graduation Year

2023

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Chemistry

Major Professor

Bill J. Baker, Ph.D.

Committee Member

H. Lee Woodcock, Ph.D.

Committee Member

Theresa Evans-Nguyen, Ph.D.

Committee Member

Kendra Daly, Ph.D.

Committee Member

Wayne Guida, Ph.D.

Keywords

Candida spp., epigenetically modified fungi, Marine natural products, SARS-CoV-2 proteases inhibitors, vATPase inhibitors

Abstract

The biodiversity of our global marine ecosystems provides substantial treasure to discover: chemistry. Marine organisms that live in proximity to one another use their unique chemistry to compete with one another and thrive in their environment. Benthic invertebrates, specifically, that lack physical means of protection will produce secondary metabolites as a means of defense from their surroundings and predators. The compounds which they produce are ordinarily species-specific, highly diverse biomolecules. Biosynthetic processes within an organism construct these secondary metabolites from fragments of primary metabolites (amino acids, fatty acids, sugars, and so on). Their roles in protection have antibiotic, toxic, and other ecological effects on their surroundings. For this reason, they are valuable starting points for pharmaceutical therapeutics.

Methods for evaluating these molecules against biological targets for the purpose of drug discovery include a variety of screening techniques. The computational power to do fast, high throughput testing of small molecules is a great advantage for the pursuit of discovering a drug lead. Methods such as this are described as in silico¬ screening, where vast libraries of secondary metabolites are observed binding with biological targets in a simulated environment to determine likelihood of potential interactions. In vitro screening, on the other hand, is a screening method where the molecules are physically interacting with cells, biomolecules, or microorganisms to observe their direct effects.

In this thesis, both methods are implemented to identify marine natural products with exceptional activity against several very prevalent pathogens that threaten our health. Covid 19, a disease caused by the SARS-CoV-2 coronavirus, is examined using both in silico¬ and invitro screening methods. Several marine natural products were identified to have potent activity against the viral main protease as well as cells infected with the virus. Candida albicans and Candida auris are two deadly, opportunistic species of yeast which commonly show drug resistance to current antifungals on the market. A large in vitro screening of FDA approved drugs was used to map the drug-susceptibility of forty different Candida strains. Additionally, testing FDA approved vATPase inhibitors and natural products identified potent inhibitory activity against Candida. Lastly, investigation of an epigenetically modified marine endophytic fungus from Tapachula, Mexico uncovered two new meroterpenoid natural products which were biochemically screened against various pathogens in vitro.

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