Antifungal activity of kigelia africana phytochemicals against cryptococcus neoformans

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Cryptococcus neoformans is an opportunistic fungal pathogen which frequently causes cryptococcosis in immunocompromised individuals all over the world. Each year, approximately one million cases of cryptococcosis are reported worldwide, resulting in increased mortality. Cryptococcosis can be treated with a limited number of antifungal drugs, with amphotericin B and fluconazole being the preferred choices. The main challenge faced in the current treatment strategy for cryptococcosis is the development of antifungal resistance by C. neoformans. A different approach is therefore necessary to identify and develop novel antifungal drugs and targets. The traditional approach for antifungal drug development has been to target the growth of the pathogen but a potentially effective alternative would be to target the virulence factors. Virulence factors are the elements of a pathogen that can cause damage in the host and lead to disease progression. They are not deemed essential for cell survival and as such are exposed to less evolutionary pressures. The most recognized virulence factors of C. neoformans include the enzyme urease, synthesis of melanin, thermotolerance, and the production of a polysaccharide capsule. In a recent study, bioactive molecules were used to inhibit cryptococcal urease activity. In Chapter 1, literature based on the classification, life cycle, geographic distribution as well as pathogenicity and virulence factors of C. neoformans is reviewed. This is followed by reviewing literature on the current treatment strategies for cryptococcosis, antifungal drug resistance mechanisms of C. neoformans and the role of plant extracts as prospects in antifungal therapy. In Chapter 2 differentially extracted Kigelia africana crude extracts were screened for their antifungal activity against C. neoformans. Ethanolic extracted crude extracts were selected as the best performing bioactives. A sub-lethal concentration of the crude extracts was established and used for the treatment of C. neoformans in the enzyme and biofilm assays. Laccase and urease activity were inhibited. Biofilm formation was inhibited, and pre-formed biofilms were disrupted. Metabolic activity of cryptococcal biofilms was significantly reduced. The effect of treating C. neoformans with K. africana crude extracts on the expression of virulence associated genes was evaluated in Chapter 3. The expression of COX1, LAC1, and URE1 was upregulated, whilst the expression of CAP10 was downregulated. 4 The findings of this study reveal evidence that K. africana crude extracts indeed have antifungal and antivirulence effects against C. neoformans and can therefore be used in the development of novel antifungal drugs which can be used to treat cryptococcal infections
A research report submitted in partial fulfilment of the requirements for the degree Master of Science to the Faculty of Science, School of Molecular and Cell Biology, University of the Witwatersrand, Johannesburg, 2023
Cryptococcus neoformans, Cryptococcosis