| Author | Oliveira, Haroldo C | |
| Author | Santos, Marlon D.M | |
| Author | Camillo-Andrade, Amanda C | |
| Author | Castelli, Rafael F | |
| Author | Reis, Flavia C.G | |
| Author | Carvalho, Paulo C | |
| Author | Rodrigues, Marcio L | |
| Access date | 2024-12-11T01:46:20Z | |
| Available date | 2024-12-11T01:46:20Z | |
| Document date | 2024 | |
| Citation | OLIVEIRA, H. C. et al. Proteomics reveals that the antifungal activity of fenbendazole against Cryptococcus neoformans requires protein kinases. INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS, v. 63, n. 107157, p. 1-10, 2024. | en_US |
| ISSN | 0924-8579 | en_US |
| URI | https://www.arca.fiocruz.br/handle/icict/67528 | |
| Description | All experimental procedures were performed with approval from the Ethics Committee on Animal Use (CEUA) of the Fundação Oswaldo Cruz, FIOCRUZ (license number LW36-19 under the protocol number P-24/19-3), and in accordance with the guidelines presented by the National Council for the Control of Animal Experimentation (CONCEA). | en_US |
| Sponsorship | M.L.R was supported by grants from the Brazilian Ministry of Health (Ministerio da Saúde, grant 440015/2018-9), and
Conselho Nacional de Desenvolvimento Científico e Tecnologico (CNPq; grants 304998/2022-2 and 405520/2018-2). | en_US |
| Language | eng | en_US |
| Publisher | Elsevier | en_US |
| Rights | restricted access | |
| Subject in Portuguese | Cryptococcus neoformans | en_US |
| Subject in Portuguese | Atividade antifúngica | en_US |
| Subject in Portuguese | Fenbendazol | en_US |
| Subject in Portuguese | Proteômica | en_US |
| Subject in Portuguese | Proteínas quinases | en_US |
| Title | Proteomics reveals that the antifungal activity of fenbendazole against Cryptococcus neoformans requires protein kinases | en_US |
| Type | Article | |
| DOI | 10.1016/j.ijantimicag.2024.107157 | |
| Abstract | Cryptococcus neoformans is responsible for over 100 000 deaths annually, and the treatment of this fungal disease is expensive and not consistently effective. Unveiling new therapeutic avenues is crucial. Previous studies have suggested that the anthelmintic drug fenbendazole is an affordable and nontoxic candidate to combat cryptococcosis. However, its mechanism of anticryptococcal activity has been only superficially investigated. In this study, we examined the global cellular response of C. neoformans to fenbendazole using a proteomic approach (data are available via ProteomeXchange with identifier PXD047041). Fenben dazole treatment mostly impacted the abundance of proteins related to metabolic pathways, RNA pro cessing, and intracellular traffic. Protein kinases, in particular, were significantly affected by fenbendazole treatment. Experimental validation of the proteomics data using a collection of C. neoformans mutants led to the identification of critical roles of five protein kinases in fenbendazole’s antifungal activity. In fact, mutants lacking the expression of genes encoding Chk1, Tco2, Tco3, Bub1, and Sch9 kinases demonstrated greater resistance to fenbendazole compared to wild-type cells. In combination with the standard anti fungal drug amphotericin B, fenbendazole reduced the cryptococcal burden in mice. These findings not only contribute to the elucidation of fenbendazole’s mode of action but also support its use in combina tion therapy with amphotericin B. In conclusion, our data suggest that fenbendazole holds promise for further development as an anticryptococcal agent. | en_US |
| Affilliation | Fundação Oswaldo Cruz. Instituto Carlos Chagas. Curitiba, PR, Brasil. | en_US |
| Affilliation | Fundação Oswaldo Cruz. Instituto Carlos Chagas. Curitiba, PR, Brasil / Institut Pasteur de Montevideo. Analytical Biochemistry and Proteomics Unit. IIBCE. Montevideo, Uruguay. | en_US |
| Affilliation | Fundação Oswaldo Cruz. Instituto Carlos Chagas. Curitiba, PR, Brasil / Institut Pasteur de Montevideo. Analytical Biochemistry and Proteomics Unit. IIBCE. Montevideo, Uruguay. | en_US |
| Affilliation | Fundação Oswaldo Cruz. Instituto Carlos Chagas. Curitiba, PR, Brasil. | en_US |
| Affilliation | Fundação Oswaldo Cruz. Instituto Carlos Chagas. Curitiba, PR, Brasil / Fundação Oswaldo Cruz. Centro de Desenvolvimento Tecnológico em Saúde. Rio de Janeiro, RJ, Brasil. | en_US |
| Affilliation | Fundação Oswaldo Cruz. Instituto Carlos Chagas. Curitiba, PR, Brasil. | en_US |
| Affilliation | Fundação Oswaldo Cruz. Instituto Carlos Chagas. Curitiba, PR, Brasil / Universidade Federal do Rio de Janeiro. Instituto de Microbiologia Paulo de Góes. Rio de Janeiro, RJ, Brasil. | en_US |
| Subject | Cryptococcus neoformans | en_US |
| Subject | Antifungal activity | en_US |
| Subject | Fenbendazole | en_US |
| Subject | Proteomics | en_US |
| Subject | Protein kinases | en_US |
| DeCS | Proteínas Quinases | en_US |
| DeCS | Proteômica | en_US |
| DeCS | Cryptococcus neoformans | en_US |
| DeCS | Fenbendazol | en_US |
| Embargo date | 2034-12-31 | |
