Repurposed amitriptyline hydrochloride against fluconazole-resistant Candida albicans targeting efflux pump Pdr5, an ABC transporter: In vitro and in silico study with clinical validation.

The emergence of fluconazole-resistant Candida albicans poses a significant therapeutic challenge requiring alternative antifungal agents for treatment options. This study repurposed the antifungal potential of amitriptyline hydrochloride (AMP), a tricyclic antidepressant, against fluconazole-resistant C. albicans strain SC5314. The antifungal activity was evaluated using agar well diffusion and agar cup assays at a concentration of 2 mg/mL. Minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) assays were performed to quantify efficacy, complemented by time kill kinetics. Antibiofilm and catalase activity assays were conducted alongside wound healing experiments to assess therapeutic effects. Scanning electron microscopy revealed ultrastructural damage, including hyphal disruption, cytoplasmic leakage, and cell wall deformation in treated fungal cells. Molecular docking studies supported the interaction of AMP with key fungal targets, corroborating its mode of action, probably by inhibiting efflux pump targeting Pdr5, an ABC transporter. The overall results demonstrate that AMP exerts significant antifungal effects against fluconazole resistant C. albicans, disrupting biofilm formation and promoting wound healing in vivo, and also overcoming to fight fluconazole resistant clinical isolates. These findings suggest that AMP holds promise as an alternative therapeutic strategy for managing resistant candidiasis and warrant further investigation in clinical settings.