| Author | Oliveira, Haroldo Cesar de | |
| Author | Santos, Marlon Dias Mariano dos | |
| Author | Andrade, Amanda Caroline Camillo de | |
| Author | Castelli, Rafael Fernando | |
| Author | Reis, Flavia Coelho Garcia dos | |
| Author | Carvalho, Paulo Costa | |
| Author | Rodrigues, Marcio Lourenço | |
| Access date | 2024-10-04T18:56:51Z | |
| Available date | 2024-10-04T18:56:51Z | |
| Document date | 2024 | |
| Citation | OLIVEIRA, Haroldo Cesar de et al. Proteomics reveals that the antifungal activity of fenbendazole against Cryptococcus neoformans requires protein kinases. International Journal of Antimicrobial Agents, v. 63, n. 5, p. 1-10, May 2024. | |
| ISSN | 0924-8579 | |
| URI | https://www.arca.fiocruz.br/handle/icict/66321 | |
| Description | Supplementary material associated with this article can be found, in the online version, at doi: 10.1016/j.ijantimicag.2024.107157. | |
| Sponsorship | Marcio Lourenço Rodrigues was supported by grants from the Brazilian Ministry of Health (Ministério da Saúde, grant 440015/2018-9), and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; grants 304998/2022-2 and 405520/2018-2). | |
| Language | eng | en_US |
| Publisher | Elsevier | |
| Rights | restricted access | |
| 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). Fenbendazole treatment mostly impacted the abundance of proteins related to metabolic pathways, RNA processing, 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 antifungal 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 combination 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. | |
| Affilliation | Fundação Oswaldo Cruz. Instituto Carlos Chagas. Curitiba, PR, Brasil / Instituto de Investigaciones Biológicas Clemente Estable. Institut Pasteur de Montevideo. Analytical Biochemistry and Proteomics Unit. Montevideo, Uruguay. | |
| Affilliation | Fundação Oswaldo Cruz. Instituto Carlos Chagas. Curitiba, PR, Brasil / Instituto de Investigaciones Biológicas Clemente Estable. Institut Pasteur de Montevideo. Analytical Biochemistry and Proteomics Unit. Montevideo, Uruguay. | |
| Affilliation | Fundação Oswaldo Cruz. Instituto Carlos Chagas. Curitiba, PR, Brasil. | |
| Affilliation | Fundação Oswaldo Cruz. Instituto Carlos Chagas. Curitiba, PR, Brasil / Fundação Oswaldo Cruz. Centro de Desenvolvimento Tecnológico em Saúde. Rio de Janeiro, RJ, Brasil. | |
| Affilliation | Fundação Oswaldo Cruz. Instituto Carlos Chagas. Curitiba, PR, Brasil. | |
| Affilliation | Fundação Oswaldo Cruz. Instituto Carlos Chagas. Curitiba, PR, Brasil / Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Microbiologia Paulo de Góes. Rio de Janeiro, RJ, Brasil. | |
| Subject | Cryptococcus neoformans | en_US |
| Subject | Antifungal activity | en_US |
| Subject | Fenbendazole | en_US |
| Subject | Proteomics | en_US |
| Subject | Protein kinases | en_US |
| DeCS | Cryptococcus neoformans | pt_BR |
| DeCS | Fenbendazol | pt_BR |
| DeCS | Proteômica | pt_BR |
| DeCS | Proteínas Quinases | pt_BR |
| e-ISSN | 1872-7913 | |
| xmlui.metadata.dc.subject.ods | 03 Saúde e Bem-Estar | |
| xmlui.metadata.dc.subject.ods | 09 Indústria, inovação e infraestrutura | |
