Transcriptional profile of Paracoccidioides spp. in response to itraconazole
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2014
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Resumo
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.
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Paracoccidioides spp., Transcriptional response, Itraconazole, Ergosterol
Citação
SILVA NETO, Benedito Rodrigues da; CARVALHO, Patrícia Fernanda Zambuzzi; BAILÃO, Alexandre Melo; MARTINS, Wellington Santos; SOARES, Célia Maria de Almeida; PEREIRA, Maristela. Transcriptional profile of Paracoccidioides spp. in response to itraconazole. BMC Genomics, London, v. 15, n. 254, p. 1-15, 2014.