Date of Award

Fall 12-15-2023

Level of Access Assigned by Author

Open-Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology

Advisor

Robert Wheeler

Second Committee Member

Melody N. Neely

Third Committee Member

Melissa Maginnis

Additional Committee Members

Joshua Kelly

Clarissa Henry

Abstract

Polymicrobial infections pose a significant challenge in the field of medicine due to our incomplete understanding of how pathogens interact during infection and how these interactions impact the effectiveness of drug treatments. Among the opportunistic pathogens, Candida albicans and Pseudomonas aeruginosa stand out, as they are often found in similar infection sites, such as burn wounds, the lungs of patients with cystic fibrosis and those on mechanical ventilation. Candida albicans is an opportunistic fungus responsible for invasive candidiasis, a condition associated with a high mortality rate of 40% in hospitals. Pseudomonas aeruginosa, on the other hand, is the primary pathogen responsible for respiratory tract infections in cystic fibrosis patients. Coinfection with both pathogens is linked to a poorer prognosis and reduced lung function. The challenge in treating Candida albicans infections is exacerbated by the limited availability of antifungal agents, some of which lack fungicidal activity. Among these treatments, fluconazole (FLC), a fungicidal drug, is widely used. In this study, we examined the effectiveness of antifungal treatment in the context of C. albicans-P. aeruginosa co-culture in vitro and co-infection in a zebrafish swimbladder infection model, which serves as an analogue to lung infections. Our research demonstrates that P. aeruginosa enhances the efficacy of FLC, facilitating both the clearance of C. albicans during in vivo co-infection and fungal eradication in vitro. This synergistic effect between FLC treatment and bacterial antagonism is partially attributed to iron piracy. Furthermore, our results suggest that the P.a.-FLC combination may impact the calcineurin pathway, potentially playing an early role in limiting the P. aeruginosa-FLC synergy against C. albicans. Our study illustrates that FLC exhibits enhanced efficacy in clinically relevant scenarios, emphasizing the importance of comprehending antimicrobial effectiveness within the intricate context of the host and its associated microbial communities.

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