Journal Article

Thioridazine inhibits gene expression control of the cell wall signaling pathway (CWI) in the human pathogenic fungus Paracoccidioides brasiliensis

Vilas Boas, Renata Ozelami, Reno, Débora Liliane Souza, Santos, Daiene Souza, Nunes, Luiz R., Costa de Oliveira, Regina, Barbosa, David Aciole, Jabes, Daniela Leite, de Oliveira Rodrigues Cunha, Rodrigo Luiz, Menegidio, Fabiano Bezerra, Rodrigues, Tiago, Alencar, Valquíria Campos, de Freitas Oliveira, Ana Claudia

2016

Overview

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.

• Publisher: Springer Nature B.V
• Subject: animal pathogenic fungi / anti-infective properties / Antimicrobial agents / beta-glucans / biogenesis / Cell Wall - drug effects / Cell Wall - genetics / cell walls / chitin / data collection / Drug resistance / drug therapy / drugs / Fungal infections / Fungal Polysaccharides - biosynthesis / Fungal Proteins - genetics / Fungi / Gene expression / Gene Expression Profiling - methods / Gene Expression Regulation, Fungal - drug effects / genes / Genomics / Humans / Latin America / microarray technology / Microbial Sensitivity Tests / Microorganisms / mycoses / Oligonucleotide Array Sequence Analysis - methods / Paracoccidioides - drug effects / Paracoccidioides - genetics / Paracoccidioides brasiliensis / Paracoccidioidomycosis - drug therapy / phenothiazine / phenotype / signal transduction / Signal Transduction - drug effects / Thioridazine - pharmacology / yeasts