Discovery of the effects of the hemiprotonic phenanthroline-phenanthroline+ against Trichophyton rubrum by inducing fungal apoptosis

Trichophyton rubrum (T. rubrum) is the commonest causative agent of dermatophytosis worldwide. Development of anti-fungal drugs will contribute to treating the disease. Here we suggest a hemiprotonic compound phenanthroline- phenanthroline+ (ph-ph+), is active in inhibiting the growth and reproduction of T. rubrum, and the values of MIC and MFC were 2 g/mL and 8 g/mL, respectively. In vitro onychomycosis model, ph-ph+ killed T. rubrum by inducing apoptosis, evaluated by TEM and Annexin V-FITC/PI staining. Transcriptomic analysis and biochemical assay showed that ph-ph+ elevated iron ion content in T. rubrum cells and reduced GSH antioxidant system level, leading to increase in the contents of ROS and MDA. Therefore, the anti-fungal mechanism of ph-ph+ would be associated with iron ion-induced cell apoptosis, which is different from other known anti-fungal drugs. Further, ph-ph+ was prepared into gel for application in guinea pigs with dermatophytosis caused by T. rubrum. The results showed that the ph-ph+ gel eliminated the fungus in the animals, without skin irritation and other adverse reactions. The study would not only provide potential compound to treat dermatophytosis, but also suggests that iron ion-induced cell apoptosis might be a new approach to kill fungi.