Investigating the potential of Succinate dehydrogenase as an anti-fungal drug target in Candida glabrata

Candida glabrata is an opportunist human fungal pathogen which causes disease in immuno-compromised patients and is highly drug resistant to commonly prescribed anti-fungal drugs such as Fluconazole. This project tested whether Lonidamine (LND) has potential as a new antifungal agent. LND has shown to be safe in the mouse model so suggests it can be used in humans and has also recently been shown to inhibit Succinate dehydrogenase (complex II of the mitochondrial respiratory chain). LND caused a reduction in the C. glabrata biofilm and its ability to form colonies. Flocculation during growth assays suggested that LND causes disruptions of the cell wall. Respirometry analysis suggested LND does not utilise the ETC when SDH is inhibited and relies on the compensatory metabolic pathway known as the glyoxylate cycle. Through S. cerevisiae mutant studies, weak points within metabolic pathways were found to be ICL1 (within the glyoxylate cycle) and LSC2 (within the TCA cycle). Future research on combinational drug therapy of using LND alongside inhibitors of ICL1 or LSC2 would be crucial.