Utilizing Peptoids to Combat Microbial Infections

dc.contributor.advisor Bicker, Kevin L
dc.contributor.author Green, Robert Madison
dc.contributor.committeemember Miller, Justin
dc.contributor.committeemember Dunlap, Norma
dc.contributor.committeemember Farone, Mary
dc.contributor.committeemember Nelson, David
dc.contributor.committeemember Robertson, James B
dc.date.accessioned 2021-04-20T01:01:52Z
dc.date.available 2021-04-20T01:01:52Z
dc.date.issued 2021
dc.date.updated 2021-04-20T01:01:52Z
dc.description.abstract Candida albicans remains the number one nosocomial infection to this day. Infections by Candida albicans include thrush, vaginal candidiasis, and candidemia, which has a 40-60% mortality in healthy individuals. C. albicans main virulence factor is the formation of a polysaccharide 3D matrix called a biofilm. Biofilms protect the pathogen from administered antifungal compounds as well as the innate host immune response. Antimicrobial peptides (AMPs) are released by the host in response to infection and are being explored as antifungals but make poor final drugs due to poor bioavailability and short half-lives. Peptoids, or N-substituted glycines, are a promising peptidomimetic due to increased half-life, increased stability towards proteases, and similar side chain functionality. Herein, we explore peptoids as antifungal compounds through rational design and high throughput screening of combinatorial libraries. Peptoid derivatives of a series of ultra-short lipophilic AMPs demonstrated the ability of peptoids to maintain antimicrobial efficacy and cytotoxicity properties while vastly improving on protease stability. Peptoids were undegraded after 24 hours while peptides were completely degraded within an hour. RMG8-8 was identified using the Peptoid Library Agar Diffusion (PLAD) assay screened against C. albicans. This peptoid shows promise with excellent activity against Cryptococcus neoformans and a selectivity ratio of 120 when compared to HepG2 liver cell toxicity. RMG8-8 was shown to kill half the population of viable fungi cells within seven minutes compared to four to six hours for the clinical antifungal drug, amphotericin B. Some adjustments to the PLAD assay allowed screening of combinatorial libraries against C. albicans biofilms, resulting in the iPLAD assay, which was used to discover RMG9-11. RMG9-11 shows promise as a broad-spectrum anti-Candida compound by maintaining similar MIC values (6.25-12.5 µg/mL) across clinical strains of C. albicans and multiple Candida species, including C. auris, a multidrug resistant species of Candida. A highly beneficial feature of RMG9-11 was the lack of observed resistance development when C. albicans was repeatedly exposed to RMG9-11. This research demonstrates the utility and benefit of peptoids in the treatment of pathogenic fungal species.
dc.description.degree Ph.D.
dc.identifier.uri https://jewlscholar.mtsu.edu/handle/mtsu/6415
dc.language.rfc3066 en
dc.publisher Middle Tennessee State University
dc.source.uri http://dissertations.umi.com/mtsu:11421
dc.subject Candida albicans
dc.subject Microbial infections
dc.subject Peptoids
dc.subject Chemistry
dc.thesis.degreelevel doctoral
dc.title Utilizing Peptoids to Combat Microbial Infections
License bundle
Now showing 1 - 1 of 1
No Thumbnail Available
0 B
Item-specific license agreed upon to submission