Azoles: Mode of Antifungal Action and Resistance Development. Effect of Miconazole on Endogenous Reactive Oxygen Species Production in Candida albicans

The synthetic class of azole antimycotics constitutes the largest group of antifungal agents currently in clinical use. Widespread use of azoles has led to the rapid development of multiple drug resistance, which poses a major hurdle in antifungal therapy. The generally accepted mode of action of azoles is the inhibition of 14α-lanosterol demethylase, a key enzyme in ergosterol biosynthesis, resulting in depletion of ergosterol and accumulation of toxic 14α-methylated sterols in membranes of susceptible yeast species. For some azoles, their antifungal mode of action is not only characterized by inhibition of ergosterol biosynthesis. Recently, it was shown that generation of reactive oxygen species (ROS) is important for the antifungal activity of miconazole, pointing to an ancillary mode of action for this azole. We further analysed the effect of other azole antifungals on ROS generation in Candida albicans and could demonstrate that only miconazole induces ROS production in C. albicans. Furthermore, we show that the miconazole induced ROS production is probably caused by inhibition of the enzymes implicated in breakdown of peroxide radicals and hydrogen peroxide, i.e. peroxidase and catalase. Interestingly, only miconazole was found to exert its antifungal effect in a fungicidal way. In conclusion, further development of novel azole antimycotics, based on the chemical structure of miconazole and on its related ROS inducing capacity/fungicidal activity would be an interesting approach to address the problem of resistance occurrence.