Award Date

December 2017

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Chemistry and Biochemistry

First Committee Member

Ernesto V. Abel-Santos

Second Committee Member

Ronald K. Gary

Third Committee Member

Bryan L. Spangelo

Fourth Committee Member

Jefferson W. Kinney

Number of Pages

194

Abstract

Clostridium difficile infection (CDI) is a major cause of antibiotic-associated diarrhea. In 2011, over 500,000 patients were diagnosed with CDI in the United States and over 29,000 people died of CDI-related complications. With an average of $35,000 to treat a single case of inpatient CDI, cost burden to the healthcare system can reach up to $3.2 billion annually. As both hospital- and community-acquired CDI incidences rise due to the emergence of hypervirulent strains and CDI reoccurrences of up to 25%, standard treatments are rendered less effective and new methods of prevention are critical.

CDI is caused by bacteria called Clostridium difficile. A key characteristic of Clostridium difficile is its ability to form tough and dormant structures called spores. The spores’ dormant nature allows them to survive in the gastrointestinal tract of susceptible patients without showing any signs of infection. When the spores are under stress, they can germinate into toxin-producing cells that cause symptomatic infection.

Clostridium difficile spore germination is promoted by the bile salt taurocholate with the amino acid glycine. Another naturally-occurring bile salt called chenodeoxycholate (CDCA) can compete with taurocholate to inhibit spore germination. These bile salts are regulated by the indigenous gut microbiota. However, for patients who are immunocompromised or who have recently taken antibiotics, the composition of natural intestinal microflora can become altered, making bile salt regulation much less efficient, thus allowing spore germination to occur.

Previously, CamSA, a synthetic bile salt analog of taurocholate, was found to be a more potent germination inhibitor than CDCA when tested against epidemic type X strain 630. Currently, a new analog called 07C revealed to be a stronger germination inhibitor than CamSA in strain 630 as well as in various other strains. Plated germination inhibition assays showed that 07C inhibited spore germination in several strains of C. difficile using less than 50 μM of compound. Furthermore, mice challenged with each of the C. difficile strains had significantly reduced CDI symptoms or were completely protected from CDI symptoms when given three doses of 50 mg/kg 07C. From these explorations, bile salt analogs have the potential to serve as CDI prophylactic treatments in antibiotic-treated patients.

Keywords

antibiotic-associated diarrhea; bacterial spores; bile salts; CDI; hospital-acquired infections; spore germination

Disciplines

Biochemistry | Biology | Microbiology

Language

English


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