Author ORCID Identifier

https://orcid.org/0000-0001-7316-9331

Date of Graduation

8-2021

Document Type

Thesis (MS)

Program Affiliation

Biomedical Sciences

Degree Name

Masters of Science (MS)

Advisor/Committee Chair

Michael C. Lorenz

Committee Member

Danielle A. Garsin

Committee Member

Theresa M. Koehler

Committee Member

Jennifer Walker

Committee Member

William Margolin

Abstract

Candida albicans, the most clinically significant fungal pathogen, commonly causes topical mucosal infections such as oral cavity and urogenital tract infections. It also less frequently causes severe invasive and bloodstream infections. Invasive infections are most prevalent amongst patients with compromised innate immune responses, such as those receiving chemotherapy or recovering from surgery. C. albicans can also form biofilms on implanted medical devices. Fungal infections are difficult to treat due to the paucity of therapeutic options, and this problem is compounded by the resistance properties of biofilm infections.

Candida albicans exists as a member of the commensal flora of the skin and gut where many complex polymicrobial interactions occur with genera such as Pseudomonas and Streptococcus. Some of these interactions potentiate or inhibit virulence. One such interaction is with Enterococcus faecalis, a bacterial gastrointestinal commensal species. E. faecalis produces a small peptide, EntV, that modulates C. albicans virulence. The mature 68-amino acid EntV peptide inhibits biofilm formation in vitro and attenuates fungal virulence in a Caenorhabditis elegans infection model and a murine oral candidiasis model.

In this work, I sought to identify the regions of EntV responsible for the anti-fungal activity, and based on structural information, I hypothesized that the activity is localized to a single helix of the mature peptide. In this study, I report that smaller peptides derived from this helix ranging from 12 to 16 amino acids have equal or improved efficacy in inhibiting C. albicans virulence and biofilm formation. These smaller peptides inhibit initial adhesion to abiotic surfaces, reduce final biofilm biomass, and reduce the size of mature biofilms as measured by confocal microscopy. Further trimming of these peptides to fewer than 11 amino acids reduces and eventually eliminates activity. These data indicate that EntV-derived peptides warrant further investigation as potential non-fungicidal additives to medical devices and antifungal therapeutics.

Keywords

Candida albicans, biofilms, EntV, antimicrobial peptides, bacteriocins, candidiasis, hyphae

Available for download on Saturday, July 30, 2022

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