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Antimicrobial Agents and Chemotherapy, July 2004, p. 2483-2489, Vol. 48, No. 7
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.7.2483-2489.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Candida glabrata erg1 Mutant with Increased Sensitivity to Azoles and to Low Oxygen Tension

Huei-Fung Tsai,1 Martin Bard,2 Koichi Izumikawa,1 Anna A. Krol,1 Aaron M. Sturm,2 Nicholas T. Culbertson,2 Charles A. Pierson,2 and John E. Bennett1*

Clinical Mycology Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892,1 Department of Biology, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana 462022

Received 8 January 2004/ Returned for modification 10 March 2004/ Accepted 18 March 2004

A Candida glabrata erg1 (Cgerg1) mutant, CgTn201S, was identified by transposon mutagenesis and by increased fluconazole susceptibility. CgERG1 encodes a 489-amino-acid protein which, on the basis of its homology with Saccharomyces cerevisiae ERG1, is a squalene epoxidase essential for ergosterol synthesis. Interruption following codon 475 of CgErg1p decreased the ergosterol content by 50%; caused accumulation of the squalene precursor; increased the levels of susceptibility to fluconazole, itraconazole, and terbinafine; increased the level of resistance to amphotericin B; increased the levels of rhodamine 6G and [3H]-fluconazole uptake; reduced the level of growth; and blocked growth under conditions of low oxygen tension. In addition, CgTn201S efficiently took up exogenous cholesterol from cholesterol-containing serum. Cholesterol constituted 34% of the extractable sterols in CgTn201S when it was grown aerobically on serum-containing medium. Under the same conditions, C. albicans contained only 0.1 to 1.2% cholesterol. Exogenous sterols also restored growth under conditions of low oxygen tension. Finally, complementation of the Cgerg1 mutation restored the levels of [3H]fluconazole uptake and drug susceptibility to wild-type levels.

* Corresponding author. Mailing address: Clinical Center, Room 11C304, NIH, Bethesda, MD 20892. Phone: (301) 496-3461. Fax: (301) 480-0050. E-mail: Jbennett{at}niaid.nih.gov.

Antimicrobial Agents and Chemotherapy, July 2004, p. 2483-2489, Vol. 48, No. 7
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.7.2483-2489.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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