Characterization of Compounds with Novel Bioactivity Against the Fungal Pathogens Candida albicans and Cryptococcus neoformans
Year: 2022
Type: dissertation
Abstract: Systemic fungal diseases represent an overlooked global health burden, whose treatment is challenged by a limited antifungal armamentarium and the emergence of drug resistance. This research encompasses two complementary strategies to bolster the antifungal drug pipeline: rational optimization of existing antifungal scaffolds, and phenotype-forward screening with subsequent mode of action identification to discover novel antifungal targets. First, I evaluated in vitro target engagement, bioactivity against the fungal pathogen Cryptococcus neoformans, and mammalian cytotoxicity for over 70 analogs of a previously validated Hsp90 inhibitor scaffold. Through these structure-activity relationship (SAR) analyses, I identified several lead molecules with improved whole-cell activity and fungal target selectivity. Then, I also performed preliminary characterization of nine molecules with novel antifungal bioactivity identified from prior large- scale chemical screening. I outlined their spectrum of activity, mammalian cytotoxicity, and putative molecular target(s) via chemogenomic profiling, identifying NP-BTA as a potent and selective inhibitor of Candida albicans glutaminyl-tRNA synthetase.
Source: TSpace (University of Toronto)
Author: Xue, Alice
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7036701071