Inactivation of Sterol Δ 5,6 -Desaturase Attenuates Virulence in Candida albicans
Open Access
- 1 September 2005
- journal article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 49 (9), 3646-3651
- https://doi.org/10.1128/aac.49.9.3646-3651.2005
Abstract
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 Δ 5,6 -desaturase, involved in ergosterol synthesis. Extraction and analysis of the sterols from both isolates confirmed the absence of sterol Δ 5,6 -desaturase activity. Although the loss of sterol Δ 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.Keywords
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