Development of Fungal-Specific Stress Response Inhibitors for the Treatment of Fungal Infections
Drug resistance of medically relevant microorganisms poses a grave threat to human health and has severe economic consequences. Fungal pathogens pose an additional complication as they are closely related to their human host. Current therapies to treat fungal infections are limited and drug resistance has already emerged in the clinic. We have conducted extensive research on fungal drug resistance mechanisms and propose to target these mechanisms in combination with existing antifungals. Specifically, our aim is to target a key regulator of fungal drug resistance, the molecular chaperone Hsp90. Through a structure-guided drug design approach, fungal-selective Hsp90 inhibitors will be designed followed by chemical synthesis. We will further characterize these compounds for fungal-selectivity, enhanced efficacy, and minimal impact on human Hsp90. This work addresses the urgent unmet need for effective new antifungal therapeutics that act by a previously unexploited mode of action.