Author ORCID Identifier

https://orcid.org/0000-0001-7928-9705

Year of Publication

2020

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Pharmacy

Department

Pharmaceutical Sciences

First Advisor

Dr. Sylvie Garneau-Tsodikova

Abstract

Human fungal pathogens cause a range of diseases from benign skin conditions (i.e., ringworm) to thrush, mucosal membrane infections, and life-threatening systemic infections including bloodstream infections (i.e., aspergillosis and candidiasis) and Cryptococcal meningitis. These systemic infections occur most often in immunocompromised individuals and have high mortality rates. Current antifungal agents used in the clinic belong to three main classes: the polyenes (e.g., amphotericin B (AmB)), the echinocandins (e.g., caspofungin (CFG)), and the azoles (e.g., fluconazole (FLC)). In addition, the antimetabolite pyrimidine analogue flucytosine is used in combination with AmB. The three main classes class of antifungals each target different aspects of cell wall synthesis or cell membrane function and each class has different strengths and weaknesses depending on the strains of fungi that they are effective against, their route of administration, and their potential side effects. Problems associated with current antifungals include toxicity to patients, only effective against a limited spectrum of fungal strains, and the development of resistance of fungal strains to treatment. Discovering new antifungal therapies is a promising strategy to decrease mortality rates. Herein, three classes of molecules are evaluated for their potential as novel antifungals and reveal that (i) the antihistamines, terfenadine (TERF) and ebastine (EBA) improve the efficacy of azole antifungals when used in combination against a range of Candida strains, (ii) square-planar gold(I)-phosphine complexes exhibit broad-spectrum antifungal activity, and (iii) fluorinated aryl- and heteroaryl-substituted monohydrazones display broad-spectrum activity against fungi with little toxicity to mammalian cells, and (iv) other classes of molecules in recent literature that have shown antifungal activity. This work serves to identify promising scaffolds for novel classes of antifungals with the ultimate goal of bringing newer and more effective antifungals to be used clinically for systemic fungal infections.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2020.506

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