Biomedical Engineering ETDs

Publication Date

Summer 7-17-2017

Abstract

Candida species are the cause of many bloodstream infections through contamination of indwelling medical devices. These infections account for a 40% mortality rate, posing a significant risk to immunocompromised patients. Traditional treatments against Candida infections include amphotericin B and various azole treatments. Unfortunately, these treatments are associated with high toxicity, and resistant strains have become more prevalent. As a new frontier, light-activated phenylene ethynylenes have shown promising biocidal activity against Gram-positive and -negative bacterial pathogens, as well as the environmental yeast, Saccharomyces cerevisiae. In this thesis, we monitored the viability of Candida species after treatment with a cationic conjugated polymer (PPE) or oligomer (OPE) by flow cytometry in order to explore the antifungal properties of these compounds. The oligomer was found to disrupt Candida albicans yeast membrane integrity independent of light-activation, while the PPE is only able to do so in the presence of light, allowing for some control as to the manner which cytotoxic effects are exhibited. Furthermore, treatment with PPE-DABCO unmasked Candida albicans β-glucan, and increased phagocytosis by Dectin-1-expressing HEK-293 cells.Additionally OPE exhibited potent antifungal activity against Candida albicans and Candida parapsilosis, two medically significant fungal pathogens. In contrast, another major Candida species pathogen, Candida glabrata, displayed intrinsically low susceptibility to OPE, relative to C. ablicans and C. parapsilosis. In C. glabrata, the primary mechanism of azole-resistance is attributed to alterations in the ERG11 gene and over-expression of the CgCDR1 efflux pump gene. We hypothesize that similar mechanisms may account for C. glabrata resistance to OPE. We monitored the susceptibility of C. glabrata to OPE by flow cytometry after treatment with clorgyline, a broad spectrum efflux pump inhibitor. Clorgyline showed synergy with OPE in type strain ATCC2001. In summary, cationic phenylene ethynylenes show promising biocidal activity against pathogenic Candida spp. alone and in combination with clorgyline.

Document Type

Thesis

First Committee Member (Chair)

Aaron Neumann

Second Committee Member

David Whitten

Third Committee Member

Eva Chi

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