During the long-term usage of the azole drug for antifungal therapy in aspergillosis, emergence of azole resistant isolates of Aspergillus fumigatus has been recently documented. One of the possible mechanisms of azole resistance is the up-regulation of genes encoding drug efflux pumps, mainly belonging to ABC transporters. However, the mechanism that regulates ABC transporter gene expression has not been elucidated in filamentous fungi including Aspergillus species. In Aspergillus oryzae, until now we have shown that overexpression of a transcription regulator gene atrR positively regulates expression of ABC transporter genes (atrA, atrF, and atrG) leading to azole drug resistance. In this study, expression of atrR and the three ABC transporter genes was induced by azole drug added in the wild-type strain. Furthermore, addition of azole drug significantly enhanced the expression level of the ABC transporter genes in an overexpression strain of atrR, although equal amount of the atrR transcript was accumulated in the strain irrespective of addition of azole drug. In contrast, in an atrR deletion mutant, no expression of the above mentioned ABC transporter genes was observed regardless of the presence of azole. In Saccharomyces cerevisiae and Candida glabrata, xenobiotic substrates such as azole drugs have recently been shown to directly bind and activate the transcription regulator Pdr1p via a nuclear-receptor-like pathway. Also in A. oryzae, AtrR protein may be activated by azole drugs through a similar mechanism to accelerate the gene expression of ABC transporter genes to survive in such an environment.
Full conference title:
10th EUROPEAN CONFERENCE ON FUNGAL GENETICS
- ECFG 10th (2010)