Avaliação da atividade in vitro do ácido tranexâmico e da hidroquinona como adjuvantes em isolados clínicos de cromoblastomicose causada por Fonsecaea pedrosoi

Abstract

Chromoblastomycosis (CBM), a chronic subcutaneous mycosis caused by melanized fungi such as Fonsecaea pedrosoi, was included in 2017 in the list of Neglected Tropical Diseases by the World Health Organization (WHO), highlighting the urgent need for advances in diagnosis and treatment. Currently, the drug of choice is itraconazole (ITR), although therapeutic response remains limited, even when combined with other drugs or treatment modalities. Melanin, a key component of the F. pedrosoi cell wall, is associated with increased virulence and resistance to antifungal therapy. Notably, the melanin biosynthesis pathway in humans and fungi is highly conserved. In this context, the present study evaluated, in vitro, the effect of hydroquinone (HQN) and tranexamic acid (ATX)—depigmenting agents commonly used in the treatment of melasma—on two clinical isolates of F. pedrosoi (FpJW and FpBR), both individually and in combination with ITR. Furthermore, in silico molecular docking analysis was conducted to assess the interaction of ATX with targets in the melanin synthesis pathway, compared to HQN and kojic acid (KOJ). Minimum inhibitory concentrations (MICs) and minimum fungicidal concentrations (MFCs) of the compounds were determined by broth microdilution with visual inspection. The interaction between ITR and HQN was evaluated using the Checkerboard assay. The MIC of ITR was 2 μg/mL for FpJW and 0.5 μg/mL for FpBR. HQN, although not a conventional antifungal, exhibited cytotoxic and fungicidal activity with MIC and MFC values of 780 μg/mL for both isolates. The combination of HQN and ITR produced an additive effect, with a 50% reduction in HQN MIC and a reduction in ITR MIC of up to 1/32 for FpJW and 1/16 for FpBR. These findings provide the first evidence of HQN activity against F. pedrosoi, supporting its potential use as an adjuvant in the treatment of CBM. Additionally, due to its topical route of administration and demonstrated fungicidal activity, HQN may be considered as a standalone treatment in specific clinical scenarios, such as in patients with hepatic impairment where systemic therapies are contraindicated. The combination therapy may also reduce treatment duration, further supporting the potential drug repurposing of HQN for CBM. An in silico analysis revealed that ATX interacts with melanogenesis targets in a binding pattern like that of HQN and KOJ, suggesting direct inhibitory activity on melanin biosynthesis. These findings support the continued therapeutic use of ATX in melasma and contribute to a better understanding of its molecular mechanism, which remains underexplored in literature. To the best of our knowledge, this is the first study to demonstrate the in vitro potential of hydroquinone as an adjuvant in the treatment of chromoblastomycosis. Given its topical use, low cost, and well-established safety profile, HQN emerges as a promising therapeutic alternative. These innovative findings expand the therapeutic landscape for CBM and underscore the importance of drug repurposing in the context of neglected diseases. Moreover, this is the first study to compare the in silico activity of ATX with that of KOJ and HQN, demonstrating a direct action on the melanin biosynthetic pathway and providing new insights into its widely reported clinical effects.