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Dissertation
Molecular basis for benzimidazole susceptibility and resistance in the opportunistic yeasts Cryptococcus neoformans and Candida albicans
Doctor of Philosophy (Ph.D.), Allegheny University of the Health Sciences
Jul 1997
DOI:
https://doi.org/10.17918/00009235
Abstract
The last twenty years have witnessed a dramatic increase in fungal infections, especially those affecting immunocompromised patients. Opportunistic pathogens such as Cryptococcus neoformans and Candida albicans have proven to be of great medical importance, not only because of their high incidence rate but also due to the life threatening diseases that they cause. Current antifungal therapies are characterized by high toxicity, failure, and resistance; thus there is a need for discovery of new antifungals with improved activity. This thesis examines the potential use of benzimidazoles to treat infections caused by the basidiomycete yeast C. neoformans. The research was focused on three areas: first, the determination of the in vitro anticryptococcal activity of benzimidazoles, followed by the characterization of C. neoformans [beta]-tubulin genes as targets for benzimidazole action, and finally the analysis of acquired resistance to these drugs. As an initial step in exploring the anticryptococcal potential of benzimidazoles we examined the in vitro activity of eleven derivatives against various C. neoformans clinical isolates. We found that their level of activity varied from non active to highly active; benzimidazoles were found to be not only highly inhibitory but also fungicidal. The cryptococcal [beta]-tubulin genes (TUB1 and TUB2) were then characterized to examine the hypothesis that [beta]-tubulin is the target for benzimidazole binding, through which these compounds disrupt microtubule polymerization. Comparison of these two genes with [beta]-tubulin sequences from benzimidazole-resistant and sensitive organisms, and identification of mutations in the TUB1 gene from independently isolated benzimidazole-resistant mutants, suggests that TUB1 is the basis for the benzimidazole susceptibility of C. neoformans. Resistance to benzimidazoles in C. neoformans seems to arise through different mechanisms, including modifications oF the drug's target and through a multidrug resistance (mdr) mechanism. Mdr was demonstrated to be not only more efficient in creating benzimidazole resistance in C. neoformans but it has previously been correlated in Candida albicans with resistance to the ergosterol synthesis inhibitor fluconazole. Candida albicans which is responsible for serious localized and invasive infections in immunocompromised individuals, is naturally resistant to benzimidazole derivatives. We have found an antagonistic effect between benzimidazoles (albendazole and benomyl) and fluconazole in C. albicans that was associated with the induction of a protein involved in a multidrug efflux mechanism. This observation has clinical implications in patients where both inhibitors, albendazole and fluconazole, are used together; e.g., in some AIDS patients.
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Details
- Title
- Molecular basis for benzimidazole susceptibility and resistance in the opportunistic yeasts Cryptococcus neoformans and Candida albicans
- Creators
- Maria Cristina Cruz
- Awarding Institution
- Allegheny University of the Health Sciences
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Allegheny University of the Health Sciences; Philadelphia, Pennsylvania
- Number of pages
- x, 98 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Microbiology and Immunology [Historical]; Allegheny University of the Health Sciences (1996-1998); School of Medicine (1996-1998)
- Other Identifier
- 991021888763304721