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Defining Mechanisms of Antifungal Resistance in Cryptococcus neoformans by Quantitative Proteomics

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Title: Defining Mechanisms of Antifungal Resistance in Cryptococcus neoformans by Quantitative Proteomics
Author: Bermas, Arianne
Department: Department of Molecular and Cellular Biology
Program: Molecular and Cellular Biology
Advisor: Geddes-McAlister, Jennifer
Abstract: Cryptococcus neoformans, an opportunistic yeast-like fungal pathogen, has demonstrated resistance to all major classes of antifungal drugs, including fluconazole – the mainstay treatment of cryptococcosis. To provide mechanistic insight into fluconazole resistance, this study utilized quantitative proteomics to identify significant differences in protein abundance between fluconazole-resistant and fluconazole-susceptible strains of C. neoformans. From this data, the gene encoding a protein of interest, ClpX, was identified and further explored. Biolistic transformation combined with double joint homologous recombination was used to construct clpXΔ (CNAG_01343) knockouts. Mutant strains were phenotypically characterized to determine a role for ClpX in fungal virulence and involvement in antifungal resistance. Our results reveal that ClpX has an influence on the expression of key virulence factors. Additionally, we demonstrated that ClpX inhibition may display a synergistic effect with fluconazole and could act as a novel therapeutic strategy to reintroduce antifungal susceptibility in resistant C. neoformans strains. Overall, this work shows how ClpX, a previously uncharacterized protein in C. neoformans, contributes to virulence factor expression and antifungal resistance to fluconazole.
URI: https://hdl.handle.net/10214/26492
Date: 2021-09
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