Novel antifungal therapies using azoles and bisphosphonates

Abstract

The emergence of fungal infections and rising rates of antifungal resistance demand the urgent exploration of novel antifungal targets. Prior work showed that FPPS was upregulated in response to fluconazole, so it was hypothesised that inhibiting FPPS with bisphosphonates may synergistically enhance the activity of fluconazole. This thesis therefore aimed to 1) investigate synergy between azoles and bisphosphonates; 2) interrogate any mechanisms of activity; and 3) develop modified bisphosphonate derivatives with improved activity. In Cryptococcus, several FDA-approved bisphosphonates significantly improved the efficacy of fluconazole in vitro and in an in vivo nematode model. This synergy was attributed to simultaneous inhibition of the mevalonate and ergosterol biosynthesis pathways. Expanding this work in Candida revealed particularly strong antifungal activity and synergy in C. glabrata caused by the inhibition of squalene synthesis, resulting in sterol depletion, compromised membrane integrity and disrupted active efflux. In vivo, azole