Affiliation:
1. University Hospital Lausanne (CHUV), CH-1011 Lausanne, Switzerland
2. Pfizer Global Research and Development, Sandwich, Kent CT13 9NJ, United Kingdom
Abstract
ABSTRACT
The role of sterol mutations in the resistance of
Candida albicans
to antifungal agents has not been thoroughly investigated. Previous work reported that clinical
C. albicans
strains resistant to both azole antifungals and amphotericin B were defective in
ERG3
, a gene encoding sterol Δ
5,6
-desaturase. It is also believed that a deletion of the lanosterol 14α-demethylase gene,
ERG11
, is possible only under aerobic conditions when
ERG3
is not functional. We tested these hypotheses by creating mutants by targeted deletion of the
ERG3
and
ERG11
genes and subjecting those mutants to antifungal susceptibility testing and sterol analysis. The homozygous
erg3
/
erg3
mutant created, DSY1751, was resistant to azole derivatives, as expected. This mutant was, however, slightly more susceptible to amphotericin B than the parent wild type. It was possible to generate
erg11
/
erg11
mutants in the DSY1751 background but also, surprisingly, in the background of a wild-type isolate with functional
ERG3
alleles under aerobic conditions. This mutant (DSY1769) was obtained by exposure of an
ERG11
/
erg11
heterozygous strain in a medium containing 10 μg of amphotericin B per ml. Amphotericin B-resistant strains were obtained only from
ERG11
/
erg11
heterozygotes at a frequency of approximately 5 × 10
−5
to 7 × 10
−5
, which was consistent with mitotic recombination between the first disrupted
erg11
allele and the other remaining functional
ERG11
allele. DSY1769 was also resistant to azole derivatives. The main sterol fraction in DSY1769 contained lanosterol and eburicol. These studies showed that
erg11
/
erg11
mutants of a
C. albicans
strain harboring a defective
erg11
allele can be obtained in vitro in the presence of amphotericin B. Amphotericin B-resistant strains could therefore be selected by similar mechanisms during antifungal therapy.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Cited by
318 articles.
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