Elucidating the Underlying Genetic Mechanisms Conferring Antifungal Resistance in the Human Pathogenic Fungus Mucor circinelloides

Date
2023
Authors
Garcia, Alexis E.
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Abstract

Fungal infections plague at least 13 million people globally and are responsible for 1.5 million deaths per year. One of the largest hurdles faced when treating fungal infections is the lack of antifungal treatment options. Many fungal infections, such as mucormycosis, have an unacceptably high mortality rate due to the lack of treatments available for infected patients. Mucormycosis is a fungal infection caused by fungi in the order Mucorales. In this dissertation we studied the model Mucorales Mucor circinelloides (Mucor) to uncover how this organism can circumvent treatment by one of the latest class of antifungals, echinocandins. In this study we aim to uncover the underlying mechanisms responsible for the drug resistance observed in Mucor. The first part of this study delves into a unique response to the treatment by echinocandins seen in Mucor. Echinocandins work by inhibiting the synthesis of the fungal cell wall by non-competitively binding to the enzyme  β-1,3-glucan synthase. When inhibited, the upkeep of the cell wall is halted and the fungal cells rupture. In Mucor, we observe an overexpression of the drug target resulting in resistance to this drug. This unique response led us to the second part of this study where we began to unravel the underlying genetic mechanisms responsible for this overexpression. Calcineurin is a protein phosphatase known to have many roles in fungal morphology and stress responses. In this part of the study, we began to understand the role that calcineurin plays in the resistance to echinocandins we observe in Mucor.

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Keywords
Fungal infections, Mucormycosis, Antifungal resistance, Mucor circinelloides
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Department
Molecular Microbiology and Immunology