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postgraduate thesis: A novel antifungal for Candida infections : its in vitro and in vivo efficacy and proposed mechanism of action

TitleA novel antifungal for Candida infections : its in vitro and in vivo efficacy and proposed mechanism of action
Authors
Advisors
Issue Date2013
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Wong, S. S. [黃思華]. (2013). A novel antifungal for Candida infections : its in vitro and in vivo efficacy and proposed mechanism of action. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5177331
AbstractCandida is the major fungal pathogen in humans that causes infections from superficial mucosal to systemic mycoses. In recent years, the incidence of Candida infections has increased due to the growing body of immunocompromised host populations. In addition, shifting of species distribution and the emergence of antifungal resistance have caused frequent treatment failure. These key issues highlight an urgent need for new antifungals. In such a quest, this research involved a high-throughput screening of a library of 50,240 small molecules for yeast-to-hypha transition inhibitors, to identify and characterize novel small molecules with antifungal properties. From the highthroughput screening, 20 novel small molecules were identified as yeast-to-hypha inhibitors. Their antifungal and anti-biofilm properties were further examined with a wide range of Candida species. Following the extensive screening assays, SM21, which demonstrated the most potent antifungal activity, was selected as the final hit compound. Subsequently, SM21 was evaluated comprehensively for its in vitro and in vivo efficacy. In vitro, SM21 displayed strong inhibition of yeast-to-hypha transition at low concentrations and under hyphae-inducing conditions for a wide range of reference and clinical Candida strains. Moreover, SM21 exhibited anti-biofilm activity and also anti-adhesion activity of Candida on denture acrylic surfaces. With regard to the high prevalence of denture stomatitis, a new denture material incorporating SM21 was produced and evaluated. The SM21-incorporated denture material exhibited anti-adhesion activity and steadily released SM21 in a time-dependent manner. SM21 was also shown to be non-cytotoxic in vitro and in vivo. In vivo efficacy of SM21 was examined in systemic and oral candidiasis mouse models. SM21 treatment was successful in reducing mortality rate and fungal burden of the organs in the systemic candidiasis mouse model. SM21 treatment significantly reduced tongue lesions in the oral candidiasis mouse model. Lastly, the mechanism of action of SM21 was examined by transcriptomics (microarray) and proteomics approaches (label-free quantitative mass spectrometry). The expression of genes and proteins involved in the synthesis of components of the Candida cell wall and plasma membrane were significantly modulated by SM21. Hence, it was proposed that SM21 targets both the Candida cell wall and plasma membrane. In conclusion, the newly discovered small molecule, SM21, which possesses potent in vitro and in vivo efficacy, appears to be potentially a promising agent in managing Candida infections.
DegreeDoctor of Philosophy
SubjectCandidiasis - Treatment
Antifungal agents
Dept/ProgramDentistry
Persistent Identifierhttp://hdl.handle.net/10722/196483

 

DC FieldValueLanguage
dc.contributor.advisorSeneviratne, CJ-
dc.contributor.advisorSamaranayake, LP-
dc.contributor.authorWong, Sze-wah, Sarah-
dc.contributor.author黃思華-
dc.date.accessioned2014-04-11T23:14:29Z-
dc.date.available2014-04-11T23:14:29Z-
dc.date.issued2013-
dc.identifier.citationWong, S. S. [黃思華]. (2013). A novel antifungal for Candida infections : its in vitro and in vivo efficacy and proposed mechanism of action. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5177331-
dc.identifier.urihttp://hdl.handle.net/10722/196483-
dc.description.abstractCandida is the major fungal pathogen in humans that causes infections from superficial mucosal to systemic mycoses. In recent years, the incidence of Candida infections has increased due to the growing body of immunocompromised host populations. In addition, shifting of species distribution and the emergence of antifungal resistance have caused frequent treatment failure. These key issues highlight an urgent need for new antifungals. In such a quest, this research involved a high-throughput screening of a library of 50,240 small molecules for yeast-to-hypha transition inhibitors, to identify and characterize novel small molecules with antifungal properties. From the highthroughput screening, 20 novel small molecules were identified as yeast-to-hypha inhibitors. Their antifungal and anti-biofilm properties were further examined with a wide range of Candida species. Following the extensive screening assays, SM21, which demonstrated the most potent antifungal activity, was selected as the final hit compound. Subsequently, SM21 was evaluated comprehensively for its in vitro and in vivo efficacy. In vitro, SM21 displayed strong inhibition of yeast-to-hypha transition at low concentrations and under hyphae-inducing conditions for a wide range of reference and clinical Candida strains. Moreover, SM21 exhibited anti-biofilm activity and also anti-adhesion activity of Candida on denture acrylic surfaces. With regard to the high prevalence of denture stomatitis, a new denture material incorporating SM21 was produced and evaluated. The SM21-incorporated denture material exhibited anti-adhesion activity and steadily released SM21 in a time-dependent manner. SM21 was also shown to be non-cytotoxic in vitro and in vivo. In vivo efficacy of SM21 was examined in systemic and oral candidiasis mouse models. SM21 treatment was successful in reducing mortality rate and fungal burden of the organs in the systemic candidiasis mouse model. SM21 treatment significantly reduced tongue lesions in the oral candidiasis mouse model. Lastly, the mechanism of action of SM21 was examined by transcriptomics (microarray) and proteomics approaches (label-free quantitative mass spectrometry). The expression of genes and proteins involved in the synthesis of components of the Candida cell wall and plasma membrane were significantly modulated by SM21. Hence, it was proposed that SM21 targets both the Candida cell wall and plasma membrane. In conclusion, the newly discovered small molecule, SM21, which possesses potent in vitro and in vivo efficacy, appears to be potentially a promising agent in managing Candida infections.-
dc.languageeng-
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)-
dc.relation.ispartofHKU Theses Online (HKUTO)-
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subject.lcshCandidiasis - Treatment-
dc.subject.lcshAntifungal agents-
dc.titleA novel antifungal for Candida infections : its in vitro and in vivo efficacy and proposed mechanism of action-
dc.typePG_Thesis-
dc.identifier.hkulb5177331-
dc.description.thesisnameDoctor of Philosophy-
dc.description.thesislevelDoctoral-
dc.description.thesisdisciplineDentistry-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.5353/th_b5177331-

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