title: The Anti-helminthic Compound Mebendazole Has Multiple Antifungal Effects againstCryptococcus neoformans.
abstract: Cryptococcus neoformansis 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 inhibitingC. neoformansgrowth. Mebendazole and fenbendazole were the most efficient antifungals showingin vitrofungicidal 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 phagocytizedC. neoformans, affected cryptococcal biofilms profoundly and caused marked morphological alterations inC. neoformans, including reduction of capsular dimensions. Amphotericin B and mebendazole had additive anti-cryptococcal effects. Mebendazole was also active against theC. neoformanssibling species,C. gattii. To further characterize the effects of the drug a randomC. gattiimutant 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.
authors.affiliation: Laboratório de Biologia Celular de Leveduras Patogênicas, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro Rio de Janeiro, Brazil.
authors.forename: Luna S
authors.initials: LS
authors.lastname: Joffe
authors.affiliation: Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul Porto Alegre, Brazil.
authors.forename: Rafael
authors.initials: R
authors.lastname: Schneider
authors.affiliation: Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul Porto Alegre, Brazil.
authors.forename: William
authors.initials: W
authors.lastname: Lopes
authors.affiliation: Fundação Oswaldo Cruz - Fiocruz, Centro de Desenvolvimento Tecnológico em Saúde Rio de Janeiro, Brazil.
authors.forename: Renata
authors.initials: R
authors.lastname: Azevedo
authors.affiliation: Centro de Biotecnologia, Universidade Federal do Rio Grande do SulPorto Alegre, Brazil; Departamento de Biologia Molecular e Biotecnologia, Universidade Federal do Rio Grande do SulPorto Alegre, Brazil.
authors.forename: Charley C
authors.initials: CC
authors.lastname: Staats
authors.affiliation: Centro de Biotecnologia, Universidade Federal do Rio Grande do SulPorto Alegre, Brazil; Departamento de Biologia Molecular e Biotecnologia, Universidade Federal do Rio Grande do SulPorto Alegre, Brazil.
authors.forename: Lívia
authors.initials: L
authors.lastname: Kmetzsch
authors.affiliation: Centro de Biotecnologia, Universidade Federal do Rio Grande do SulPorto Alegre, Brazil; Departamento de Biologia Molecular e Biotecnologia, Universidade Federal do Rio Grande do SulPorto Alegre, Brazil.
authors.forename: Augusto
authors.initials: A
authors.lastname: Schrank
authors.affiliation: Veterans Administration Medical Center, NorthportNY, USA; Department of Molecular Genetics and Microbiology, Stony Brook University, Stony BrookNY, USA.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Del Poeta
authors.affiliation: Centro de Biotecnologia, Universidade Federal do Rio Grande do SulPorto Alegre, Brazil; Departamento de Biologia Molecular e Biotecnologia, Universidade Federal do Rio Grande do SulPorto Alegre, Brazil.
authors.forename: Marilene H
authors.initials: MH
authors.lastname: Vainstein
authors.affiliation: Laboratório de Biologia Celular de Leveduras Patogênicas, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de JaneiroRio de Janeiro, Brazil; Fundação Oswaldo Cruz - Fiocruz, Centro de Desenvolvimento Tecnológico em SaúdeRio de Janeiro, Brazil.
authors.forename: Marcio L
authors.initials: ML
authors.lastname: Rodrigues
keywords: Cryptococcus neoformans; antifungal; antifungal targets; benzimidazoles; biofilm; macrophages; mebendazole