Regulatory Mechanisms Driving Azole Antifungal Resistance

Current estimates suggest that more than 1.5 million people die of fungal diseases each year. The dark figure however seems to be much higher. A large proportion of deaths are attributed to infections caused by species of the genus Aspergillus. Treatment of the disease, generally termed aspergillosis, is limited to only three major drug classes. The most widely used antifungal agents belong to the class of azoles. Worryingly, an increase and world-wide distribution of resistance to this drug class developed into a serious threat to public health and is of particular danger for immunocompromised patients. Limited treatment options and the widespread occurrence of resistance highlight the urgent need to take action and drive forward antifungal research in order to combat fungal infections. Azole antifungal drugs inhibit an essential enzymatic reaction in ergosterol biosynthesis. Ergosterol has a similar function to cholesterol in human cells and the inhibition of this specific step, which is catalyzed by the enzyme Cyp51, blocks fungal growth. Predominant mechanisms of resistance are based on the elevated expression of Cyp51. Due to the fact that currently employed azole drugs target Cyp51, isolates with increased production of the enzyme display increased resistance to most clinically administered azoles. Over the past years, further ergosterol biosynthesis enzymes have been identified that drive resistance when their activity is increased. A central goal of this project illustrates the molecular elucidation of azole resistance mechanisms in Aspergillus. A major emphasis will be on mechanisms that are based on altered expression of ergosterol biosynthesis genes, which can be a result of mutations within regulatory DNA elements thereof. Using newly established molecular tools including a multigene expression platform in Aspergillus, a particular focus of this project is on the investigation of resistance mechanisms that underlie differential expression of multiple genes. Outcomes of this project are anticipated to contribute to the optimization and development of novel therapeutic strategies against aspergillosis.