Intrinsic azole resistance in mucormycetes

From an evolutionary point of view, the mucormycetes belong to the oldest organisms among the known fungal pathogens of humans. Diseases caused by mucormycetes are named mucormycosis. Worldwide, the incidence of invasive mucormycosis has increased in the last decade. In Europe, the incidences are 500 to 1,000 cases per year and the economic cost of this devastating and potentially lethal disease is estimated at 50 million per year. Patients having a high risk to get fungal infections (e.g., immunocompromised patients) receive antifungal drugs as a preventive measure. Commonly used agents for fungal prophylaxis are so called short-tailed azoles (e.g. voriconazole, fluconazole) and echinocandins. These substances are not active against mucormycetes, and this limits the therapeutic options dramatically. Within the azole drugs, there are substances with different molecule structures; with long-, mid- or short-tails. All mucormycetes are resistant against short-tailed azoles (fluconazole and voriconazole), mid- and long-tailed azoles are active against most mucormycetes, but have also therapeutic gaps. The underlying molecular mechanism of short-tailed azole resistance in mucormycetes is not fully understood. The target of the azole is the ergosterol biosynthetic enzyme, lanosterol 14alpha- demethylase (LDM), which is involved decisively in formation of the cell membrane of the fungi. This project aims to decipher at molecular level, why mucormycetes are resistant against short-azole drugs. We have the hypothesis that short tailed azole resistance is mediated by the drug binding region of LDM. Understanding how the structure of LDM influences azole resistance of mucormycetes is essential for novel drug development. With the structural and functional data generated we will establish a comprehensive and practical tool kit for the screening and discovery of novel broad-spectrum antifungals applicable in human medicine, veterinary medicine, and agriculture. This new generation of drugs is urgently needed to combat one of the major challenges for modern medicine - the emergence of multidrug resistant microbes.