Evaluating the activity of novel natural and synthetic antifungal agents against select pathogenic yeast
Date
2024
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Abstract
Fungal infections are believed to affect over a billion people worldwide, with more than 150 million people estimated to be suffering with serious or fatal fungal diseases. Many of these infections are caused by opportunistic fungal pathogens within the Candida and Cryptococcus genera. Current treatment options are limited, costly and can come with significant toxic side effects. This has contributed towards the emergence of novel, multidrug resistant pathogens. With the rise of microbial resistance, it is imperative that efforts are made to provide alternative antifungal treatments that are not only effective, but also non-toxic. To this end, plant based extracts and silver compounds serve as promising treatment opportunities. This study screened a variety of novel silver (I)-phosphine compounds and native plant extracts for their antifungal and antibiofilm activity against pathogens in the Candida and Cryptococcus genera. Furthermore, the toxicity of select compounds was assessed using Caenorhabditis elegans as a model organism. Lastly, the efficacy of select compounds was assessed in vivo through the use of the C. elegans infection model. In Chapter 1, important fungal pathogens within the Candida and Cryptococcus genera are examined. The difficulties associated with the treatment of systemic infections including resistance mechanisms, such as biofilm formation, employed by fungal pathogens is reviewed. The importance of the need for new antifungal treatment opportunities is stressed with silverbased molecules and plant extracts serving as promising antifungal treatment opportunities. Lastly, the use of C. elegans as a model organism to assess toxicity and efficacy of novel antifungal drugs is assessed.
In Chapter 2, seven novel silver (I)-phosphine complexes (SPC) as well as eleven native plant extracts are screened for their antifungal activity against a variety of clinically important pathogens within the Candida and Cryptococcus genera. This screening showed SPC 7 as wells as the ethanolic extracts of Hypoxis hemerocallidea, Kigelia africana and Pelargonium zonale possess promising antifungal activity. As such the minimum inhibitory and fungicidal concentrations for those compounds were determined.
Chapter 3 examines the antibiofilm properties of the K. africana extract and SPC 7 against pathogens within the Candida and Cryptococcus genera. The results demonstrated that neither of the compounds were able to prevent or disrupt biofilm formation, however when the biofilms were exposed to SPC 7, reductions in the metabolic activity of the biofilms was observed.
In Chapter 4, the toxicity of SPC 7 and the ethanolic extracts of H. hemerocallidea, K. africana and P. zonale is assessed using C. elegans as a model organism. The K. africana extract was found to be the least toxic of the plant extracts with SPC 7 also showing low levels of toxicity against the nematode. As such, the efficacy of those compounds was assessed in vivo against Candida auris and Cryptococcus neoformans infected nematodes. The infected nematodes showed significant reductions in mortality when treated with SPC 7. As such, SPC 7 was identified as a promising antifungal treatment showing potent fungistatic, fungicidal, and antibiofilm properties against Candida and Cryptococcus pathogens. Furthermore, SPC 7 shows to exhibit low toxicity towards nematodes while also improving the lifespan of C. auris and C. neoformans infected nematodes. Thus, future work should be conducted to elucidate the mechanisms of action to further assess its suitability as a novel antifungal treatment.
Description
A research report submitted in fulfilment of the requirements for the degree of Master of Science to the Faculty of Science, School of Molecular and Cell Biology, University of the Witwatersrand, Johannesburg, 2023
Keywords
Fungal infections, Pathogenic yeast, Antifungal agents