Award Date

May 2023

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry and Biochemistry

First Committee Member

Ernesto Abel-Santos

Second Committee Member

Hong Sun

Third Committee Member

Cory Rusinek

Fourth Committee Member

Allyson Hindle

Number of Pages

237

Abstract

Clostridioides difficile infection (CDI) is a major cause of antibiotic-associated diarrhea. Due to its insidious nature, the Centers for Disease Control and Prevention (CDC) has declared CDI an urgent threat. A key characteristic of C. difficile is its ability to form dormant spores that act as the infectious vehicles for disease. In the gut, spores recognize bile salts to germinate into toxin-producing cells.Dysbiosis of the gut microbiome is a key factor in allowing the C. difficile spores to germinate. Normal gut microbiota naturally protects from CDI. However, biological variables such as diet and sex have been found to modulate to the gut microbiota. Antibiotics can also disrupt the natural microbiota within the gastrointestinal tract causing dysbiosis. Thus, antibiotic use in conjunction with biological variables may influence CDI outcomes. Since spore germination is a necessary step for CDI establishment, methods that target this process could prevent infection. Recently, CaPA, an amide-based aniline-substituted anti-germinant bile salt analog, has been found to inhibit spore germination in vitro and prevent CDI in both mice and hamsters. However, it’s possible hydrolysis of the amide in the gut could release toxic byproducts. In order to address anti-germinant instability, we tested a new generation of bile salt analogs. We discovered nonhydrolyzable heterocyclic-substituted analogs that are active against multiple C. difficile strains. More importantly, a quinazoline-derivative analog (CA-Quin) and a benzothiazole-derivative (CA-BzTh) analog were able to act as murine CDI prophylactics. CDI signs can also be affected by diet and hormonal changes. In fact, we found out that macronutrient composition in diet and the estrous cycle in mice affect CDI severity. Moreover, sexual dimorphism and estrous cycle also influences CDI prophylaxis. Thus, an anti-germination approach is a promising strategy for CDI prophylaxis but can be modulated by host variables.

Keywords

antibiotic-associated diarrhea; bacterial spore germination; bile salts; biological variables; CDI; sexual dimorphism

Disciplines

Biochemistry | Biology | Microbiology

Degree Grantor

University of Nevada, Las Vegas

Language

English

Rights

IN COPYRIGHT. For more information about this rights statement, please visit http://rightsstatements.org/vocab/InC/1.0/

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