Elucidating the mode of action of Occidiofungin - a current first in class antifungal

Abstract

Fungal infections are responsible for an approximate 1.5 million deaths annually, with there being no licensed vaccines or vaccines currently in clinical study for fungal disease. This combined with the increasing resistance to the current antifungals in clinical use, highlights an ever increasing need for new antifungal research. My research aims to elucidate the mode of action of a current first in class antifungal known as Occidiofungin. This antifungal is currently undergoing clinical trials and has shown potent broad spectrum activity in the treatment of pathogenic yeast. My aim was to determine the mechanism that this drug uses in order to kill fungal cells. Previous research suggested that Occidiofungin may target the Actin cytoskeleton and as Actin is essential to cell function this may represent a plausible mode of action. I employed a range of techniques to investigate whether Occidiofungin inhibits the function of Actin and whether recognised Actin-related modes of cell death were activated. My findings suggest that Actin is not targeted but rather Occidiofungin induces necrosis in cells in a gradual manner. This finding was strengthened by observations that a fluorescent tagged Occidiofungin (Alkyne Occidiofungin) was not internalised but accumulated at the outer surface of the yeast cell. The fungal specificity of Occidiofungin was also investigated through the use of haemolysis assays and the Galleria mellonella infection model. This pre-clinical data suggested that Occidiofungin is indeed fungal specific and so is a promising candidate for use as a future therapeutic. Future research will determine the fungal specific target of Occidiofungin that is responsible for the induction of necrosis which may in turn lead to the expansion of this class of antifungal. If targeting the fungal cell wall, upon recognition of the target component, this would have broad applications both in the knowledge of the drug and proof that is has fungal specificity, it could also indicate a novel site that could be used in drug design and development