RRC ID 47069
Author Nakayama H, Tanabe K, Bard M, Hodgson W, Wu S, Takemori D, Aoyama T, Kumaraswami NS, Metzler L, Takano Y, Chibana H, Niimi M.
Title The Candida glabrata putative sterol transporter gene CgAUS1 protects cells against azoles in the presence of serum.
Journal J Antimicrob Chemother
Abstract 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.
Volume 60(6)
Pages 1264-72
Published 2007-12-1
DOI 10.1093/jac/dkm321
PII dkm321
PMID 17913716
MeSH ATP-Binding Cassette Transporters / genetics ATP-Binding Cassette Transporters / metabolism* Antifungal Agents / pharmacology* Azoles / pharmacology* Candida glabrata / drug effects* Candida glabrata / genetics Culture Media Drug Resistance, Fungal* Fluconazole / pharmacology Fungal Proteins / genetics Fungal Proteins / metabolism Gene Deletion Gene Expression Regulation, Fungal Microbial Sensitivity Tests Saccharomyces cerevisiae Proteins / genetics Sterols / metabolism* Tetracycline / pharmacology
IF 5.439
Times Cited 42
WOS Category PHARMACOLOGY & PHARMACY INFECTIOUS DISEASES MICROBIOLOGY
Resource
Pathogenic microorganisms ?