Description:

Title:

"Identifying Vulnerabilities in Fungal Pathogens Through Functional and Chemical Genomic Analyses"

Leah Cowan, PhD

Associate Vice-President, Research | University of Toronto
Professor, Department of Molecular Genetics | Temerty Faculty of Medicine

Canada Research Chair in Microbial Genomics & Infectious Disease

Co-Director, CIFAR Fungal Kingdom: Threats & Opportunities

Chief Scientific Officer, Bright Angel Therapeutics

Faculty Host:

Karla Satchell, PhD

Topic:

Microbial pathogens pose a grave threat to human health. Fungal pathogens present a particular challenge because they are eukaryotes and share many of the same biological processes as the human hosts they infect. The number of drug classes that have distinct targets in fungi is very limited and the usefulness of current antifungal drugs is compromised by dose-limiting host toxicity and the frequent emergence of high-grade resistance. New, non-cross-reactive drugs for the treatment of life-threatening fungal infections are urgently needed. Here, I discuss our recent work spanning functional and chemical genomic approaches to identify novel strategies to cripple fungal pathogens. I highlight the power of chemical genomic screens to identify novel bioactive molecules and new antifungal targets. To expand the chemical space for antifungal drug development, we explore the prospects of targeting core regulators of cellular stress response for the development of resistance-evasive combination regimens. Beyond targets essential for fungal proliferation and drug resistance, we define regulators of key virulence traits, such as the capacity for morphological transitions, and identify interkingdom interactions in the microbiota that modulate these traits. Together, this work identifies vulnerabilities in fungal pathogens and provides a strategy for leveraging structure-guided drug design to develop molecules that can distinguish pathogen from host and selectively cripple fungal pathogens.