Abstract
Cryptococcus neoformans is the most lethal pathogen of the central nervous system. The gold standard treatment of cryptococcosis, a combination of amphotericin B with 5-fluorocytosine, involves broad toxicity, high costs, low efficacy, and limited worldwide availability. Although the need for new antifungals is clear, drug research and development (R&D) is costly and time-consuming. Thus, drug repurposing is an alternative to R&D and to the currently available tools for treating fungal diseases. Here we screened a collection of compounds approved for use in humans seeking for those with anti-cryptococcal activity. We found that benzimidazoles consist of a broad class of chemicals inhibiting C. neoformans growth. Mebendazole and fenbendazole were the most efficient antifungals showing in vitro fungicidal activity. Since previous studies showed that mebendazole reaches the brain in biologically active concentrations, this compound was selected for further studies. Mebendazole showed antifungal activity against phagocytized C. neoformans, affected cryptococcal biofilms profoundly and caused marked morphological alterations in C. neoformans, including reduction of capsular dimensions. Amphotericin B and mebendazole had additive anti-cryptococcal effects. Mebendazole was also active against the C. neoformans sibling species, C. gattii. To further characterize the effects of the drug a random C. gattii mutant library was screened and indicated that the antifungal activity of mebendazole requires previously unknown cryptococcal targets. Our results indicate that mebendazole is as a promising prototype for the future development of anti-cryptococcal drugs.
Highlights
Cryptococcus neoformans is a yeast-like pathogen that causes expressive brain damage in immunosuppressed individuals (Colombo and Rodrigues, 2015)
Of the 727 drugs tested at 10 μM, 17 compounds were active against C. neoformans, including antibacterials, a neuroleptic drug, calcium channel blockers, antiarrhythmic agents, drugs for gastrointestinal malignances, gynecologic regulators, an anti-histaminic and the
We extended the results obtained with the compound collection to dose-response tests using the four benzimidazoles showing antifungal activity and other related molecules, including thiabendazole, oxibendazole, and fenbendazole
Summary
Cryptococcus neoformans is a yeast-like pathogen that causes expressive brain damage in immunosuppressed individuals (Colombo and Rodrigues, 2015). The fungus reaches the lungs of humans after inhalation of environmental cells. C. neoformans efficiently disseminates to the brain and causes meningitis (Kwon-Chung et al, 2014). Cryptococcal meningitis is a global problem resulting in thousands of deaths annually (Park et al, 2009). Most cases occur among people with HIV/AIDS. Poor and late diagnosis, limited access to antifungals and drug resistance are directly associated to the high fatality rate of cryptococcosis, especially in developing countries (Rodrigues, 2016)
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