Onychomycosis is a nail
infection caused by Trichophyton interdigitale and other fungi, which can be treated with topical
amorolfine (AMR) and
ciclopirox olamine (CPX). Although these drugs are widely used, little is known about the role of reactive
oxygen (ROS) and
nitrogen (RNS) in their mechanism of action. To better understand the effects of AMR and CPX in dermatophytes, we evaluated whether they act through the production of ROS and
peroxynitrite (PRN). We tested a set of strains, all susceptible to AMR and CPX, and these antifungals significantly reduced T. interdigitale viability within 24 h. This effect occurred concomitantly with reduced
ergosterol, increased production of ROS and PRN, and consequently increased lipid peroxidation. Together, these mechanisms lead to cell damage and fungal death. These fungicidal effects were abolished when PRN and
superoxide scavengers were used in the assays, demonstrating the role of these species in the mechanism of action. We also studied the
antioxidant system when T. interdigitale was exposed to AMR and CPX. Interestingly,
superoxide dismutase and
catalase inhibition lead to altered ROS and PRN production, lipid peroxidation, and
ergosterol levels. In fact, the combination of AMR or CPX with a
superoxide dismutase inhibitor was antagonistic. Together, these data demonstrate the importance of ROS and PRN in the antifungal action of AMR and CPX against the evaluated T. interdigitale strains.
LAY SUMMARY: