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Antimicrobial Agents and Chemotherapy, September 2005, p. 3646-3651, Vol. 49, No. 9
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.9.3646-3651.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Inactivation of Sterol ^5,6-Desaturase Attenuates Virulence in Candida albicans

Andrew S. Chau,¹ Maya Gurnani,¹ Robyn Hawkinson,¹ Michel Laverdiere,² Anthony Cacciapuoti,¹ and Paul M. McNicholas^1*

Schering Plough Research Institute, 2015 Galloping Hill Road, K15-4-4700, Kenilworth, New Jersey 07033,¹ Department of Microbiology-Infectious Diseases, Hospital Maisonneuve-Rosemont, Montreal, Quebec, Canada²

Received 12 April 2005/ Returned for modification 11 May 2005/ Accepted 26 May 2005

Two clinical Candida albicans isolates that exhibited high-level resistance to azoles and modest decreases in susceptibility to amphotericin B were cultured from unrelated patients. Both isolates harbored homozygous nonsense mutations in ERG3, which encodes an enzyme, sterol ^5,6-desaturase, involved in ergosterol synthesis. Extraction and analysis of the sterols from both isolates confirmed the absence of sterol ^5,6-desaturase activity. Although the loss of sterol ^5,6-desaturase activity is known to confer resistance to azoles, this mechanism of resistance has rarely been seen in clinical isolates, suggesting that such mutants are at a competitive disadvantage. To test this hypothesis, the virulence of the erg3 mutants was assayed by using a mouse systemic infection model. The mutants were significantly less virulent than the wild-type comparator strains. However, the kidney fungal burdens in mice infected with the erg3 mutants were similar to those in mice infected with the wild-type strains. Similar results were obtained by using a laboratory-generated homozygous erg3 deletion mutant (D. Sanglard et al., Antimicrob. Agents Chemother. 47:2404-2412, 2003). Reintroduction of a wild-type ERG3 allele into the homozygous deletion mutant restored virulence, ergosterol synthesis, and susceptibility to azoles, confirming that these phenotypic changes were solely due to the inactivation of Erg3p.

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* Corresponding author. Mailing address: Schering Plough Research Institute, K15-4-4700, 2015 Galloping Hill Road, Kenilworth, NJ 07033. Phone: (908) 740-7644. Fax: (908) 740-3918. E-mail: paul.mcnicholas{at}spcorp.com.

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Antimicrobial Agents and Chemotherapy, September 2005, p. 3646-3651, Vol. 49, No. 9
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.9.3646-3651.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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