Author ORCID Identifier
https://orcid.org/0000-0002-9808-0701
Date of Award
Summer 8-15-2024
Document Type
Thesis (Ph.D.)
Department or Program
Microbiology and Immunology
First Advisor
Robert A. Cramer
Abstract
Invasive fungal disease present are difficult to diagnose and treat and present a high mortality rate across the world with approximately 1.5 million people a year succumbing to fungal infections worldwide. Currently, there are limited antifungal classes used therapeutically, and antifungal drug resistance on the rise further exacerbates the dire need for novel therapeutics with innovative mode of actions. The filamentous fungi, Aspergillus fumigatus is the causative agent of invasive pulmonary aspergillosis (IPA). It is estimated that contemporary antifungals fail in about 50% of patients with invasive filamentous fungal infections, likely due to the biofilm mode of growth exhibited in vivo by filamentous fungi. In vitro, we have shown that as biofilms mature, the establishment of low oxygen microenvironments directly contributes to their increased antifungal resistance. The transcription factor SrbA, is essential for adaptation to low oxygen, biofilm formation, virulence, and azole resistance. Therefore, we postulated inhibition of SrbA as a potential novel therapeutic strategy to combat invasive filamentous fungal infections and azole resistance.
In this dissertation we describe a high-throughput screen to identify SrbA pathway inhibitors and further characterize the mode of action of two of the small molecule hits, MBX-7591 and MBX-7498. Both of these molecules show synergy with azoles and decrease total oleic acid content, which alters phospholipid composition. Furthermore, MBX-7591 is effective in vivo in decreasing fungal burden against A. fumigatus and R. delemar. Additionally, in this discussion we additionally studied the predicted sterol transporter ArvA in A. fumigatus and identified a putative role in the conidial transition from isotropic to polarized growth and cell wall composition.
Recommended Citation
Gutierrez Perez, Cecilia, "Targeting Aspergillus fumigatus hypoxia response pathways for novel antifungal drug development." (2024). Dartmouth College Ph.D Dissertations. 298.
https://digitalcommons.dartmouth.edu/dissertations/298
