EMPOWERING ANTIFUNGAL DRUGS DISCOVERY THROUGH THE ZEBRAFISH-INFECTIOUS DISEASES MODELLING

Abstract

Fungal infections, once considered a rare disease, have become an everyday problem in modern societies, posing major challenges to global health. It is estimated that more than one billion people are affected by fungal infections and 1.6 million people succumb to these diseases every year. Of the 600 species of fungi capable of causing infections in humans, species of the genus Candida cause more than 85% of infections, especially C. albicans, which has become a serious threat to human health in immunocompromised and immunosuppressed individuals. Unfortunately, the current arsenal of clinical drugs relies on only four classes of approved drugs (polyenes, azoles, echinocandins and allylamines), which are only partially effective, resulting in incomplete eradication of the fungal infection. In addition, the serious side effects, ranging from systemic or organ-specific toxicity to poor bioavailability and low activity, significantly hamper the clinical use of antifungals. These problems call for new effective and safe antifungal agents,but also for appropriate preclinical models to accurately study potential adverse effects on the human population and test their efficacy against fungal infections. In this sense, zebrafish (Danio rerio) embryos have become one of the most powerful preclinical animal models in infection biology and drug discovery, offering the unique opportunity to simultaneously monitor the safety and efficacy of the applied molecule in real time. With the aim of providing a preclinical platform for the identification of new safe antifungal drugs to effectively control C. albicans infection, we comprehensively tested the toxicity of 13 clinical antifungal drugs in the zebrafish embryo model. The 21 toxicity endpoints, including survival, teratogenicity, cardiotoxicity and hepatotoxicity, were evaluated and compared with adverse effects described in rats and humans. Of the clinical drugs, the efficacy of fluconazole and voriconazole was evaluated in the zebrafish - C. albicans model of systemic and wound biofilm infection.