Thioridazine inhibits gene expression control of the cell wall signaling pathway (CWI) in the human pathogenic fungus Paracoccidioides brasiliensis
Autor: | Valquíria Campos Alencar, Daniela L. Jabes, Ana Claudia de Freitas Oliveira, Daiene Souza Santos, Rodrigo L. O. R. Cunha, Regina Costa de Oliveira, David Aciole Barbosa, Luiz R. Nunes, Tiago Rodrigues, Fabiano Bezerra Menegidio, Renata Ozelami Vilas Boas, Débora L. Renó |
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Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
030106 microbiology Microbial Sensitivity Tests Biology Bioinformatics Microbiology Fungal Proteins Cell wall 03 medical and health sciences Cell Wall Gene Expression Regulation Fungal Gene expression Genetics medicine Humans Molecular Biology Gene Oligonucleotide Array Sequence Analysis Paracoccidioides brasiliensis Thioridazine Paracoccidioidomycosis Gene Expression Profiling Fungal Polysaccharides Paracoccidioides General Medicine Pathogenic fungus biology.organism_classification medicine.disease Phenotype 030104 developmental biology Signal transduction Signal Transduction |
Zdroj: | Molecular Genetics and Genomics. 291:1347-1362 |
ISSN: | 1617-4623 1617-4615 |
Popis: | Paracoccidioides brasiliensis is a thermodimorphic fungus associated with paracoccidioidomycosis (PCM), the most common systemic mycosis in Latin America. PCM treatment involves a long-term chemotherapeutic approach and relapses occur at an alarming frequency. Moreover, the emergence of strains with increased drug-resistance phenotypes puts constant pressure on the necessity to develop new alternatives to treat systemic mycoses. In this work, we show that the phenothiazine (PTZ) derivative thioridazine (TR) inhibits in vitro growth of P. brasiliensis yeasts at micromolar concentrations. We employed microarray hybridization to examine how TR affects gene expression in this fungus, identifying ~1800 genes that were modulated in response to this drug. Dataset evaluation showed that TR inhibits the expression of genes that control the onset of the cell wall integrity (CWI) response, hampering production of all major structural polysaccharides of the fungal cell wall (chitin, α-glucan and β-glucan). Although TR and other PTZs have been shown to display antimicrobial activity by various mechanisms, inhibition of CWI signaling has not yet been reported for these drugs. Thus, TR may provide a novel approach to treat fungal infections by targeting cell wall biogenesis. |
Databáze: | OpenAIRE |
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