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Dissertation
Molecular basis of resistance to sterol biosynthesis inhibitors in Candida species and Saccharomyces cerevisiae
Doctor of Philosophy (Ph.D.), Medical College of Pennsylvania and Hahnemann University
Mar 2001
DOI:
https://doi.org/10.17918/00007567
Abstract
The incidence of infection due to the yeast Candida albicans has risen dramatically over the last two decades and is due to an increase in the number of immunocompromised individuals. The most common treatment for candidiasis is the use of azole antifungals which inhibit ergosterol biosynthesis. The widespread use of these drugs in treatment and prophylaxis resulted in the emergence of resistance to this class of antifungals. Their fungistatic activity contributes to both treatment failure and the development of resistance. Relatedly, in vitro studies with C. albicans reveal tolerance, even at high azole concentrations. This thesis examines the role of transcriptional regulation of specific yeast genes potentially involved in resistance or tolerance to azoles and other sterol biosynthesis inhibitors. The research focused on three areas: (i) the role of drugs used in the treatment of opportunistic pathogens on the transcription of C. albicans multidrug efflux pumps which resulted in decreased sensitivity to azole antifungals, (ii) the transcriptional response of genes involved in ergosterol biosynthesis to inhibitors of this pathway, and (iii) the identification of factors that regulate the expression of ergosterol biosynthesis genes and consequently affect sensitivity to azoles and other inhibitors of this pathway. It was discovered that two drugs used to treat AIDS-related opportunistic infections, sulfadiazine and albendazole, increased the expression of genes encoding the C. albicans multidrug efflux pumps Cdr1p and Cdr2p. This was correlated with decreased sensitivity to azole antifungals and suggests a potential mechanism for the higher incidence of C. albicans treatment failure and resistance in AIDS patients. Inhibitors of three different enzymes involved in fungal sterol biosynthesis increased the expression of C. albicans ERG genes encoding multiple enzymes in this pathway. Tolerance to antifungals that target this pathway is often observed in Candida species, and it is likely that ERG upregulation contributes to this tolerance. Understanding the mechanisms of sterol gene regulation in yeast may provide rational approaches to reducing resistance and developing new antifungal treatments. Using the model yeast Saccharomyces cerevisae, it was found that the transcriptional repressor Rox1p plays a role in regulating ergosterol biosynthesis genes and affects sterol biosynthesis inhibitor sensitivity.
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Details
- Title
- Molecular basis of resistance to sterol biosynthesis inhibitors in Candida species and Saccharomyces cerevisiae
- Creators
- Karl Woodman Henry
- Contributors
- Thomas D. Edlind (Advisor) - Drexel University, Medical College of Pennsylvania and Hahnemann University (1993-1996, 1998-2002)
- Awarding Institution
- Medical College of Pennsylvania and Hahnemann University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Medical College of Pennsylvania and Hahnemann University; Philadelphia, Pennsylvania
- Number of pages
- xii, 145 pages, 18 unnumbered pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Medical College of Pennsylvania and Hahnemann University (1993-1996, 1998-2002)
- Other Identifier
- 991021888862404721