JAC Advance Access originally published online on October 2, 2007
Journal of Antimicrobial Chemotherapy 2007 60(6):1264-1272; doi:10.1093/jac/dkm321
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The Candida glabrata putative sterol transporter gene CgAUS1 protects cells against azoles in the presence of serum
1 Department of Chemistry and Biochemistry, Suzuka National College of Technology, Shiroko, Suzuka, Mie 510-0294, Japan 2 Department of Bioactive Molecules, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan 3 Department of Biology, Indiana University-Purdue University Indianapolis, 723 W. Michigan St., Indianapolis, IN 46202, USA 4 Department of Electronic and Information Engineering, Suzuka National College of Technology, Shiroko, Suzuka, Mie 510-0294, Japan 5 Research Center for Pathogenic Fungi and Microbial Toxicoses, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8673, Japan
Received 9 March 2007; returned 21 April 2007; revised 31 July 2007; accepted 1 August 2007
* Corresponding author. Tel: +81-59-368-1835; Fax: +81-59-368-1820; E-mail: nakayama{at}chem.suzuka-ct.ac.jp
Objectives: The uptake of endogenous sterol from serum may allow Candida glabrata to survive azole treatment. This study aims to determine the contribution of a sterol transporter that alters fluconazole sensitivity in the presence of serum.
Methods: Bioinformatic analysis predicted CgAUS1 as the C. glabrata orthologue of the Saccharomyces cerevisiae transporters AUS1 and PDR11. To investigate whether the CgAUS1 gene has sterol transporter activity, we investigated the effects of an AUS1 deletion on the growth of a tetracycline-regulatable ERG9 strain (tet-ERG9aus1), wherein ERG9 expression is turned off giving rise to a sterol requirement. Tetracycline-dependent repression of CgAUS1 in the tet-AUS1 strain was used to determine the fluconazole susceptibility of CgAUS1 in the presence and absence of serum.
Results: The tetracycline-treated tet-ERG9aus1 strain failed to grow in the presence of serum, whereas the parental tet-ERG9AUS1 strain grew by incorporating sterol from exogenously supplied serum. Serum cholesterol protected cells against the antifungal effects of fluconazole and this protection was lost by repressing CgAUS1 gene expression. Furthermore, such protection was also observed during itraconazole treatment, but not observed in cells treated with non-azole antifungals.
Conclusions: CgAUS1 appears to function as a sterol transporter that may contribute to lower azole susceptibility in the presence of serum and to protect C. glabrata against azole toxicity in vivo.
Keywords: antifungal resistance , sterol uptake , tetracycline-regulatable strain
These authors have contributed equally.
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