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

Author(s):Show less -

Jabes, Daniela Leite ^[1] ; de Freitas Oliveira, Ana Claudia ^[1] ; Alencar, Valquiria Campos ^[1] ; Menegidio, Fabiano Bezerra ^[1] ; Souza Reno, Debora Liliane ^[2] ; Santos, Daiene Souza ^[1] ; Barbosa, David Aciole ^[1] ; Vilas Boas, Renata Ozelami ^[1] ; de Oliveira Rodrigues Cunha, Rodrigo Luiz ^[2] ; Rodrigues, Tiago ^[2] ; de Oliveira, Regina Costa ^[1] ; Nunes, Luiz R. ^[2]

Affiliation

^[1] Univ Mogi das Cruzes, Nucleo Integrado Biotecnol, Av Dr Candido Xavier de Almeida Souza 200, BR-08780911 Mogi das Cruzes, SP - Brazil

^[2] Univ Fed ABC, Ctr Ciencias Nat & Humanas, Rua Santa Adelia 166, BR-09210170 Santo Andre, SP - Brazil

• Document type: Journal article
• Source: Molecular Genetics and Genomics; v. 291, n. 3, p. 1347-1362, JUN 2016.
• Web of Science Citations: 3

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 similar to 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, alpha-glucan and beta-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. (AU)

• FAPESP's process: 12/12247-8 - New applications of phenothiazines and Palladacycles: nanostructured systems to the mechanistic study of death in tumor cells
• Grantee: Tiago Rodrigues
• Support Opportunities: Regular Research Grants