Given the rise in incidence of invasive fungal infections, limited range of effective antifungal agents and increasing resistance amongst pathogenic fungi, there is an urgent need to explore novel drug targets and new antifungal agents. The fungal virulence determinant, phospholipase B (PLB) is considered to be one such a potential target for antifungal drug therapy and prompted the development of various classes of PLB inhibitors, including the bis(alkylpyridinium)alkanes compounds and miltefosine (MI), both of which have ‘lipid-like” structures.
This thesis demonstrates that the novel compounds, bis(alkylpyridinium)alkane, and especially, MI may be effective antifungal agents. Key findings were that bis(alkylpyridinium)alkanes had in vitro activity against pathogenic yeasts such as Candida spp. and Cryptococcus spp., while MI demonstrated synergistic activity against resistant moulds such as Scedosporium, Fusarium and the mucormycetes in combination with either posaconazole or voriconazole. This work also provides insight into how MI causes apoptosis-like cell death in yeast, namely via activation of the metacaspase encoded by MCA1. An efflux pump Hxt13p was also identified in yeast which when overexpressed led to MI resistance.
Further study into the antifungal properties and mechanisms will provide more useful information necessary for using such compounds to boost drug development.