Antifungal effects of paroxetine and fluoxetine, synergism with antifungal drugs, and mode of action against <i>Candida</i> spp

<i>Candida</i> spp. is an important genus associated with superficial and invasive diseases, especially in immunosuppressed patients. Although <i>C. albicans</i> is the most common species related to serious infections, non-<i>albicans</i> species have also emerged with high rates of antifungal resistance. Drug repositioning is a great alternative to reduce and control fungal resistance and infections. Paroxetine (PRX) and fluoxetine (FLX), both selective serotonin reuptake inhibitors antidepressants, are promising drugs with antifungal and antibacterial activities according to the literature, but studies exploring their mechanism of action and usage in combination with other antifungal drugs are scarce. Therefore, we evaluated the in vitro activity of PRX and FLX against <i>Candida</i> spp. The minimum inhibitory concentrations (MICs) were determined for PRX, FLX, and for the antifungals fluconazole, itraconazole, and amphotericin B (AMB), and checkerboard assay was performed to analyze the interactions between them. Furthermore, the possible mechanism of action was evaluated by flow cytometry, comet assay, measurement of protein oxidation, and determination of glutathione levels. The tested antidepressants had MIC values ranging from 8 to 128 μg/mL and mostly had synergistic interactions when combined with AMB. Additionally, their mechanisms of action can be related to the induction of severe oxidative stress that leads to apoptosis in fungal cells showing a synergistic effect when combined with AMB. Thus, the use of PRX and FLX may be an alternative to treat infections caused by resistant microorganisms, by enhanced effects at lower concentrations when combined with AMB, possibly reducing the risk of toxicity of both drugs.