Fluconazole (FLC), a triazole, is a common treatment for most prevalent opportunistic fungal infections, including candidiasis and cryptococcosis. In 2009, Cryptococcus neoformans lead to over 600,000 deaths, ranking it deadlier than tuberculosis. As the occurrence of FLC-resistant Candida albicans and Cryptococcus neoformans strains increases, the need to fully understand its mechanism of action rises. Recent papers have identified an increase in reactive oxygen species upon FLC treatment, but fail to identify their source or identity. FLC binds both iron and copper, and stabilizes Cu(I) and Fe(II) oxidation states over Cu(II) and Fe(III) as measured by cyclic voltammetry. We also investigated the effects of FLC on copper- and iron-mediated DNA damage using gel electrophoresis under biologically relevant conditions. FLC does not cause DNA damage by itself. Addition of FLC lowers the concentration of Fe(II) or Cu(I) needed to cause 50% DNA damage (IC50), increasing reactive oxygen species production. Addition of a synergistic agent such as ascorbic acid, in general, has been shown as a promising approach to increase FLC efficiency to cause DNA-damage, and its effects on FLC-metal-mediated DNA damage will be discussed.

Fluconazole needs copper or iron to generate reactive oxygen species and damage DNA

256th National Meeting (2018)

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