| Author | Reis, Thaila Fernanda dos | |
| Author | Horta, Maria Augusta Crivelente | |
| Author | Colabardini, Ana Cristina | |
| Author | Fernandes, Caroline Mota | |
| Author | Silva, Lilian Pereira | |
| Author | Bastos, Rafael Wesley | |
| Author | Fonseca, Maria Vitória de Lazari | |
| Author | Wang, Fang | |
| Author | Martins, Celso | |
| Author | Rodrigues, Marcio Lourenço | |
| Author | Pereira, Cristina Silva | |
| Author | Poeta, Maurizio del | |
| Author | Wong, Koon Ho | |
| Author | Goldman, Gustavo H. | |
| Access date | 2021-11-11T19:55:40Z | |
| Available date | 2021-11-11T19:55:40Z | |
| Document date | 2021 | |
| Citation | REIS, Thaila Fernanda dos et al. Screening of chemical libraries for new antifungal drugs against Aspergillus fumigatus reveals sphingolipids are involved in the mechanism of action of miltefosine. mBio. v. 12, n. 4, p. 1–26, 2021. | pt_BR |
| ISSN | 2150-7511 | pt_BR |
| URI | https://www.arca.fiocruz.br/handle/icict/49787 | |
| Language | por | pt_BR |
| Publisher | American Society for Microbiology | pt_BR |
| Rights | open access | pt_BR |
| Subject in Portuguese | Miltefosina | pt_BR |
| Title | Screening of chemical libraries for new antifungal drugs against Aspergillus fumigatus reveals sphingolipids are involved in the mechanism of action of miltefosine | pt_BR |
| Type | Article | pt_BR |
| DOI | 10.1128/mBio .01458-21 | |
| Abstract | Aspergillus fumigatus is an important fungal pathogen and the main etiological agent of aspergillosis, a disease characterized by a noninvasive process that can evolve to a more severe clinical manifestation, called invasive pulmonary aspergillosis (IPA), in immunocompromised patients. The antifungal arsenal to threat aspergillosis is
very restricted. Azoles are the main therapeutic approach to control IPA, but the emergence of azole-resistant A. fumigatus isolates has significantly increased over recent decades. Therefore, new strategies are necessary to combat aspergillosis, and drug repurposing has emerged as an efficient and alternative approach for identifying new antifungal drugs. Here, we used a screening approach to analyze A. fumigatus in vitro
susceptibility to 1,127 compounds. A. fumigatus was susceptible to 10 compounds, including miltefosine, a drug that displayed fungicidal activity against A. fumigatus. By screening an A. fumigatus transcription factor null library, we identified a single mutant, which has the smiA (sensitive to miltefosine) gene deleted, conferring a phenotype of susceptibility to miltefosine. The transcriptional profiling (RNA-seq) of the wild-type and
DsmiA strains and chromatin immunoprecipitation coupled to next-generation sequencing (ChIP-Seq) of an SmiA-tagged strain exposed to miltefosine revealed genes of the sphingolipid pathway that are directly or indirectly regulated by SmiA. Sphingolipid analysis demonstrated that the mutant has overall decreased levels of sphingolipids when growing in the presence of miltefosine. The identification of SmiA represents the
first genetic element described and characterized that plays a direct role in miltefosine response in fungi. | pt_BR |
| Affilliation | Universidade de São Paulo. Faculdade de Ciências Farmacêuticas de Ribeirão Preto. Ribeirão Preto, SP, Brasil. / MicroControl Innovation Ltd. Ribeirão Preto, São Paulo, Brasil. | pt_BR |
| Affilliation | Universidade de São Paulo. Faculdade de Ciências Farmacêuticas de Ribeirão Preto. Ribeirão Preto, SP, Brasil. | pt_BR |
| Affilliation | Universidade de São Paulo. Faculdade de Ciências Farmacêuticas de Ribeirão Preto. Ribeirão Preto, SP, Brasil. | pt_BR |
| Affilliation | Department of Microbiology and Immunology. Stony Brook University. Stony Brook, New York, USA. | pt_BR |
| Affilliation | Universidade de São Paulo. Faculdade de Ciências Farmacêuticas de Ribeirão Preto. Ribeirão Preto, SP, Brasil. | pt_BR |
| Affilliation | Universidade de São Paulo. Faculdade de Ciências Farmacêuticas de Ribeirão Preto. Ribeirão Preto, SP, Brasil. | pt_BR |
| Affilliation | Universidade de São Paulo. Faculdade de Ciências Farmacêuticas de Ribeirão Preto. Ribeirão Preto, SP, Brasil. | pt_BR |
| Affilliation | Faculty of Health Sciences. University of Macau. Taipa, Macau, China. | pt_BR |
| Affilliation | Universidade Nova de Lisboa. Instituto de Tecnologia Química e Biológica António Xavier. Oeiras, Portugal. | pt_BR |
| 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. | pt_BR |
| Affilliation | Universidade Nova de Lisboa. Instituto de Tecnologia Química e Biológica António Xavier. Oeiras, Portugal. | pt_BR |
| Affilliation | Department of Microbiology and Immunology. Stony Brook University. Stony Brook, New York, USA. / Veteran Administration Medical Center. Northport, New York, USA. / iMicroRid Technologies Inc. Dix Hills, New York, USA. / Division of Infectious Diseases. School of Medicine. Stony Brook University. Stony Brook, New York, USA. | pt_BR |
| Affilliation | Faculty of Health Sciences. University of Macau. Taipa, Macau, China. / Institute of Translational Medicine. Faculty of Health Sciences. University of Macau. Taipa, Macau, China. / Ministry of Education. Frontiers Science Center for Precision Oncology. University of Macau. Taipa, Macau, China. | pt_BR |
| Affilliation | Universidade de São Paulo. Faculdade de Ciências Farmacêuticas de Ribeirão Preto. Ribeirão Preto, SP, Brasil. | pt_BR |
| Subject | Drug Repositioning | pt_BR |
| Subject | Sphingolipids | pt_BR |
| Subject | Activating Transcription Factors | pt_BR |
| Subject in Spanish | Reposicionamiento de Medicamentos | pt_BR |
| Subject in Spanish | Esfingolípidos | pt_BR |
| Subject in Spanish | Factores de Transcripción Activadores | pt_BR |
| Subject in French | Repositionnement des médicaments | pt_BR |
| Subject in French | Sphingolipides | pt_BR |
| Subject in French | Facteurs de transcription ATF | pt_BR |
| DeCS | Aspergillus fumigatus | pt_BR |
| DeCS | Reposicionamento de Medicamentos | pt_BR |
| DeCS | Esfingolipídeos | pt_BR |
| DeCS | Fatores Ativadores da Transcrição | pt_BR |
