The number of patients suffering from
fungal diseases has constantly increased during the last decade. Among the fungal pathogens, the airborne filamentous fungus Aspergillus fumigatus can cause chronic and fatal invasive mold
infections. So far, only three major classes of drugs (
polyenes,
azoles, and
echinocandins) are available for the treatment of life-threatening
fungal infections, and all present pharmacological drawbacks (e.g., low solubility or toxicity). Meanwhile, clinical antifungal-resistant isolates are continuously emerging. Therefore, there is a high demand for novel antifungal drugs, preferentially those that act on new targets. We studied
urease and the accessory
proteins in A. fumigatus to determine their biochemical roles and their influence on virulence.
Urease is crucial for the growth on
urea as the sole
nitrogen source, and the transcript and
protein levels are elevated on
urea media. The
urease deficient mutant displays attenuated virulence, and its spores are more susceptible to macrophage-mediated killing. We demonstrated that this observation is associated with an inability to prevent the acidification of the phagosome. Furthermore, we could show that a
nickel-
chelator inhibits growth on
urea. The
nickel chelator is also able to reverse the effects of
urease on macrophage killing and phagosome acidification, thereby reducing virulence in systemic and trachea
infection models. IMPORTANCE The development of antifungal drugs is an urgent task, but it has proven to be difficult due to many similarities between fungal and animal cells. Here, we characterized the
urease system in A. fumigatus, which depends on
nickel for activity. Notably,
nickel is not a crucial
element for humans. Therefore, we went further to explore the role of
nickel-dependent
urease in host-pathogen interactions. We were able to show that
urease is important in preventing the acidification of the phagosome and therefore reduces the killing of conidia by macrophages. Furthermore, the deletion of
urease shows reduced virulence in murine
infection models. Taken together, we identified
urease as an essential
virulence factor of A. fumigatus. We were able to show that the application of the
nickel-
chelator dimethylglyoxime is effective in both in vitro and in vivo
infection models. This suggests that
nickel chelators or
urease inhibitors are potential candidates for the development of novel antifungal drugs.