title: Thioridazine inhibits gene expression control of the cell wall signaling pathway (CWI) in the human pathogenic fungus Paracoccidioides brasiliensis.
abstract: 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.
authors.affiliation: Núcleo Integrado de Biotecnologia, Universidade de Mogi das Cruzes (UMC), Av. Dr. Cândido Xavier de Almeida Souza, 200, Mogi das Cruzes, SP, CEP 08780-911, Brazil.
authors.forename: Daniela Leite
authors.initials: DL
authors.lastname: Jabes
authors.affiliation: Núcleo Integrado de Biotecnologia, Universidade de Mogi das Cruzes (UMC), Av. Dr. Cândido Xavier de Almeida Souza, 200, Mogi das Cruzes, SP, CEP 08780-911, Brazil.
authors.forename: Ana Claudia
authors.initials: AC
authors.lastname: de Freitas Oliveira
authors.affiliation: Núcleo Integrado de Biotecnologia, Universidade de Mogi das Cruzes (UMC), Av. Dr. Cândido Xavier de Almeida Souza, 200, Mogi das Cruzes, SP, CEP 08780-911, Brazil.
authors.forename: Valquíria Campos
authors.initials: VC
authors.lastname: Alencar
authors.affiliation: Núcleo Integrado de Biotecnologia, Universidade de Mogi das Cruzes (UMC), Av. Dr. Cândido Xavier de Almeida Souza, 200, Mogi das Cruzes, SP, CEP 08780-911, Brazil.
authors.forename: Fabiano Bezerra
authors.initials: FB
authors.lastname: Menegidio
authors.affiliation: Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Rua Santa Adélia, 166, Santo André, SP, CEP 09210-170, Brazil.
authors.forename: Débora Liliane Souza
authors.initials: DL
authors.lastname: Reno
authors.affiliation: Núcleo Integrado de Biotecnologia, Universidade de Mogi das Cruzes (UMC), Av. Dr. Cândido Xavier de Almeida Souza, 200, Mogi das Cruzes, SP, CEP 08780-911, Brazil.
authors.forename: Daiene Souza
authors.initials: DS
authors.lastname: Santos
authors.affiliation: Núcleo Integrado de Biotecnologia, Universidade de Mogi das Cruzes (UMC), Av. Dr. Cândido Xavier de Almeida Souza, 200, Mogi das Cruzes, SP, CEP 08780-911, Brazil.
authors.forename: David Aciole
authors.initials: DA
authors.lastname: Barbosa
authors.affiliation: Núcleo Integrado de Biotecnologia, Universidade de Mogi das Cruzes (UMC), Av. Dr. Cândido Xavier de Almeida Souza, 200, Mogi das Cruzes, SP, CEP 08780-911, Brazil.
authors.forename: Renata Ozelami
authors.initials: RO
authors.lastname: Vilas Boas
authors.affiliation: Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Rua Santa Adélia, 166, Santo André, SP, CEP 09210-170, Brazil.
authors.forename: Rodrigo Luiz
authors.initials: RL
authors.lastname: de Oliveira Rodrigues Cunha
authors.affiliation: Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Rua Santa Adélia, 166, Santo André, SP, CEP 09210-170, Brazil.
authors.forename: Tiago
authors.initials: T
authors.lastname: Rodrigues
authors.affiliation: Núcleo Integrado de Biotecnologia, Universidade de Mogi das Cruzes (UMC), Av. Dr. Cândido Xavier de Almeida Souza, 200, Mogi das Cruzes, SP, CEP 08780-911, Brazil.
authors.forename: Regina
authors.initials: R
authors.lastname: Costa de Oliveira
authors.affiliation: Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Rua Santa Adélia, 166, Santo André, SP, CEP 09210-170, Brazil. Luiz.Nunes@ufabc.edu.br.
authors.forename: Luiz R
authors.initials: LR
authors.lastname: Nunes
mesh_terms: D002473:Cell Wall / Q000187:drug effects / Q000235:genetics; D062610:Fungal Polysaccharides / Q000096:biosynthesis; D005656:Fungal Proteins / Q000235:genetics*; D020869:Gene Expression Profiling / Q000379:methods*; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D006801:Humans; D008826:Microbial Sensitivity Tests; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D010228:Paracoccidioides / Q000187:drug effects* / Q000235:genetics; D010229:Paracoccidioidomycosis / Q000188:drug therapy; D015398:Signal Transduction / Q000187:drug effects; D013881:Thioridazine / Q000494:pharmacology*
chemical_list: D062610:Fungal Polysaccharides; D005656:Fungal Proteins; D013881:Thioridazine
keywords: Cell wall integrity; Gene expression; Paracoccidioides brasiliensis; Phenothiazine; Thioridazine