Screening of chemical libraries for new antifungal drugs against Aspergillus fumigatus reveals sphingolipids are involved in the mechanism of action of miltefosine

dc.creatorReis, Thaila Fernanda dos
dc.creatorHorta, Maria Augusta Crivelente
dc.creatorColabardini, Ana Cristina
dc.creatorFernandes, Caroline Mota
dc.creatorSilva, Lilian Pereira
dc.creatorBastos, Rafael Wesley
dc.creatorFonseca, Maria Vitória de Lazari
dc.creatorWang, Fang
dc.creatorMartins, Celso
dc.creatorRodrigues, Marcio Lourenço
dc.creatorPereira, Cristina Silva
dc.creatorPoeta, Maurizio del
dc.creatorWong, Koon Ho
dc.creatorGoldman, Gustavo H.
dc.date2021-11-11T19:55:40Z
dc.date2021-11-11T19:55:40Z
dc.date2021
dc.date.accessioned2023-09-27T00:12:55Z
dc.date.available2023-09-27T00:12:55Z
dc.identifierREIS, 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.
dc.identifier2150-7511
dc.identifierhttps://www.arca.fiocruz.br/handle/icict/49787
dc.identifier10.1128/mBio .01458-21
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/8898592
dc.descriptionAspergillus 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.
dc.formatapplication/pdf
dc.languagepor
dc.publisherAmerican Society for Microbiology
dc.rightsopen access
dc.subjectMiltefosina
dc.subjectDrug Repositioning
dc.subjectSphingolipids
dc.subjectActivating Transcription Factors
dc.subjectReposicionamiento de Medicamentos
dc.subjectEsfingolípidos
dc.subjectFactores de Transcripción Activadores
dc.subjectRepositionnement des médicaments
dc.subjectSphingolipides
dc.subjectFacteurs de transcription ATF
dc.subjectAspergillus fumigatus
dc.subjectReposicionamento de Medicamentos
dc.subjectEsfingolipídeos
dc.subjectFatores Ativadores da Transcrição
dc.titleScreening of chemical libraries for new antifungal drugs against Aspergillus fumigatus reveals sphingolipids are involved in the mechanism of action of miltefosine
dc.typeArticle


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