UCSF

The development of effective approaches to prevent, diagnose, and treat infectious diseases is made possible through a strong basis in the fundamental biology of pathogen lifecycles as well as methods for direct discovery and validation of tools to fight infectious diseases. In this dissertation, I discuss work that was performed with the primary goal of identifying actionable countermeasure strategies against specific infectious diseases, while contributing to understanding aspects of basic pathogen biology where possible. Chapters 2 through 5 of this dissertation discuss efforts utilizing high-throughput small molecule screening to repurpose existing clinically-approved compounds as potential inhibitors of specific human pathogens. Chapters 2 and 3 describe discovery, validation, and mechanistic investigation for the novel antiviral effect of azithromycin. Chapter 4 describes a similar discovery pipeline for identification of the 8-hydroxyquinoline nitroxoline as a novel inhibitor of the brain-eating amoeba Balamuthia mandrillaris. In chapter 5, we apply a similar drug repurposing approach to validate the potent antifungal effect of another 8-hydroxyquinoline, clioquinol, against the fungal pathogen Candida auris. Chapters 6 through 10 describe studies pertaining to our team’s response to the SARS-CoV-2 pandemic. Chapter 6 details a large team effort to validate the field performance of the Abbott BinaxNOW rapid SARS-CoV-2 antigen test that is now in widespread over the counter use. This antigen test was used extensively for the study described in chapter 7, which measured the transmission dynamics of specific SARS-CoV-2 variants. Chapters 8, 9, and 10 investigate the magnitude and specificity of neutralizing antibody responses produced by individuals with prior exposure to SARS-CoV-2 variants and/or vaccines.