Date of Award

2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Biomedical Sciences

Track

Microbiology, Immunology, and Biochemistry

Research Advisor

Glen Palmer, PhD

Committee

Brian Peters, PhD; Jarrod Fortwendel, PhD; Kirk Hevener, PharMD, PhD; Todd Reynolds, PhD

Keywords

Antifungal antagonism, Candida albicans, Fungal Fitness, Host-Pathogen Interaction

Abstract

Invasive fungal infections (IFIs) are estimated to kill 1.5 million people each year with mortality rates remaining high (around 30-70%), despite the availability of three major classes of antifungal drugs. Furthermore, millions more suffer debilitating infections of the mucosal membranes or destructive subcutaneous mycoses. One of the most common IFIs is invasive candidiasis, mostly commonly caused by Candida albicans infections, with mortality rates of approximately 30%. In addition, the population of susceptible individuals and the incidences of both mucosal and systemic mycoses continue to rise due to the widespread use of broad-spectrum antibacterial agents, cancer chemotherapies, and the immune suppressive regimes necessary for organ transplantation, as well as the ongoing HIV and type 2 diabetes pandemics. The azoles remain the most important and widely used class of antifungal treatment for invasive C. albicans infections, acting through the inhibition of ergosterol biosynthesis. The polyenes, such as amphotericin B, damage the plasma membrane through direct interactions with ergosterol, while the echinocandins disrupt cell wall biosynthesis through inhibition of β-1,3 glucan synthase. However, despite multiple classes of antifungals available to treat invasive candidiasis, treatment failure rates are alarmingly high, being approximately 30%. Certainly, the increasing incidence of acquired drug resistance, as well as the emergence of species with intrinsic resistance to each of these agents, undoubtedly contributes to the high frequency of treatment failure for invasive candidiasis. However, as many as two-thirds of clinical treatment failures occur in the absence of microbiological drug resistance. A variety of factors, such as inadequate drug distribution to the site of infection or the severity of a patient’s immune dysfunction, have been proposed to contribute to this phenomenon—however, little evidence is available to support these arguments. One factor that has been overlooked is the influence of other medications taken by the patient on the fungal pathogen itself. This is especially pertinent due to the fundamental similarities between fungal and mammalian cells as eukaryotic organisms, fungi and mammals share similar cell biology and highly conserved signaling pathways. Accordingly, drugs designed to induce a physiological or biochemical response in humans may stimulate a similar response within fungal cells. These similarities have been previously exploited as the basis to identify existing drugs with antifungal activity or those that enhance the activity of currently approved antifungals. However, reciprocal efforts to systematically identify pharmacotherapies that diminish the efficacy of antifungal drugs have largely been unstudied. As such, it is possible that there are non-antifungal medications that have yet to be identified that can alter C. albicans physiology by increasing antifungal tolerance, which can ultimately diminish therapy efficacy. This is important to consider given that the number of individuals within the population receiving more than one medication has grown dramatically in recent years, and those at greatest risk of developing life-threatening fungal infections usually receive a multitude of drugs to treat a variety of underlying conditions. In accordance, we identified a variety of structurally and functionally diverse antagonists which antagonize azole and echinocandin activity on C. albicans growth, as well as drugs that alter sensitivity to the cell wall stressor Congo red. These include several drugs often taken by patients at risk for invasive candidiasis infections. One medication of interest, the anti-psychotic aripiprazole, was consistently identified as an antagonist for all screens tested, and was found to be Tac1p-dependent for azole tolerance, a zinc cluster transcription factor commonly found with gain-of-function mutations in azole resistant isolates. Surprisingly, while we observed that aripiprazole did not alter fluconazole efficacy in a disseminated mouse model of candidiasis, drug treated mice succumbed to infection earlier than untreated mice. This indicates that aripiprazole appears to alter disease progression, which can drastically impact antifungal therapy efficacy. However, we noted this interaction was dependent upon the host immune state, as this was not observed in immunosuppressed mice. Further testing revealed that during macrophage challenges, aripiprazole supplementation alters production of key pro-inflammatory cytokines such as TNF-α and IL-1β. These results suggest aripiprazole changes the host-pathogen interaction. Overall, the work in this study provides a proof-of-principle that non-antifungal drugs can alter C. albicans physiology as well as the host-pathogen interaction, and further research is warranted into better understanding how this may impact antifungal therapy efficacy.

Declaration of Authorship

Declaration of Authorship is included in the supplemental files.

ORCID

0009-0008-4216-7294

DOI

10.21007/etd.cghs.2024.0667

Additional Files
2024-011-Reitler DOA.pdf (104 kB)
Declaration of Authorship
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