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Open Access Research article

Transcriptional profile of Paracoccidioides spp. in response to itraconazole

Benedito Rodrigues da Silva Neto1, Patrícia Fernanda Zambuzzi Carvalho1, Alexandre Melo Bailão1, Wellington Santos Martins2, Célia Maria de Almeida Soares1 and Maristela Pereira1*

Author Affiliations

1 Departamento de Bioquímica e Biologia Molecular, Laboratório de Biologia Molecular, Instituto de Ciências Biológicas, ICBII, Campus II, Universidade Federal de Goiás, C.P. 131, 74001-970 Goiânia, GO, Brazil

2 Instituto de Informática, Universidade Federal de Goiás, Goiânia, Goiás, Brazil

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BMC Genomics 2014, 15:254  doi:10.1186/1471-2164-15-254

Published: 1 April 2014

Abstract

Background

Itraconazole is currently used to treat paracoccidioidomycosis. The mechanism of action of azoles has been elucidated in some fungi, although little is known regarding its mechanism of action in Paracoccidioides spp. The present work focused on identification of regulated transcripts using representational difference analysis of Paracoccidioides spp. yeast cells treated with itraconazole for 1 and 2 h.

Results

Paracoccidioides Pb01 genes up-regulated by itraconazole included genes involved in cellular transport, metabolism/energy, transcription, cell rescue, defense and virulence. ERG11, ERG6, ERG3, ERG5 and ERG25 were up-regulated at multiple time points. In vivo infection experiments in mice corroborated the in vitro results. Ergosterol levels and distribution were evaluated in Paracoccidioides Pb18 yeast cells, and the results demonstrate that both factors were changed in the fungus treated with itraconazole.

Conclusion

To our knowledge, this is the first transcriptional analysis of Paracoccidioides spp. exposed to a triazole drug. Here acetyl seems to be intensively produced from different metabolic pathways to produce ergosterol by the action of ergosterol synthesis related enzymes, which were also affected in other fungi. Among the genes affected, we identified genes in common with other fungi, as well as genes unique to Paracoccidioides Pb01. Those genes could be considered target to new drugs. Voltage-gated Ca2+ alpha subunit (CAV), Tetracycline resistance protein (TETA) and Hemolisyn-iii channel protein (HLYiii) were found only here and a probably involvement with resistence to itraconazole could be investigated in the future. However our findings do not permit inference to current clinical practice.

Keywords:
Paracoccidioides spp.; Transcriptional response; Itraconazole; Ergosterol