Reduced Susceptibility to Polyenes Associated with a Missense Mutation in the ERG6 Gene in a Clinical Isolate of Candida glabrata with Pseudohyphal Growth
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Medientyp:
E-Artikel
Titel:
Reduced Susceptibility to Polyenes Associated with a Missense Mutation in the ERG6 Gene in a Clinical Isolate of Candida glabrata with Pseudohyphal Growth
Erschienen:
American Society for Microbiology, 2007
Erschienen in:
Antimicrobial Agents and Chemotherapy, 51 (2007) 3, Seite 982-990
Sprache:
Englisch
DOI:
10.1128/aac.01510-06
ISSN:
0066-4804;
1098-6596
Entstehung:
Anmerkungen:
Beschreibung:
<jats:title>ABSTRACT</jats:title>
<jats:p>
Little information is available about the molecular mechanisms responsible for polyene resistance in pathogenic yeasts. A clinical isolate of
<jats:italic>Candida glabrata</jats:italic>
with a poor susceptibility to polyenes, as determined by disk diffusion method and confirmed by determination of MIC, was recovered from a patient treated with amphotericin B. Quantitative analysis of sterols revealed a lack of ergosterol and an accumulation of late sterol intermediates, suggesting a defect in the final steps of the ergosterol pathway. Sequencing of Cg
<jats:italic>ERG11</jats:italic>
, Cg
<jats:italic>ERG6</jats:italic>
, Cg
<jats:italic>ERG5</jats:italic>
, and Cg
<jats:italic>ERG4</jats:italic>
genes revealed exclusively a unique missense mutation in Cg
<jats:italic>ERG6</jats:italic>
leading to the substitution of a cysteine by a phenylalanine in the corresponding protein. In addition, real-time reverse transcription-PCR demonstrated an overexpression of genes encoding enzymes involved in late steps of the ergosterol pathway. Moreover, this isolate exhibited a pseudohyphal growth whatever the culture medium used, and ultrastructural changes of the cell wall of blastoconidia were seen consisting in a thinner inner layer. Cell wall alterations were also suggested by the higher susceptibility of growing cells to Calcofluor white. Additionally, complementation of this isolate with a wild-type copy of the Cg
<jats:italic>ERG6</jats:italic>
gene restored susceptibility to polyenes and a classical morphology. Together, these results demonstrated that mutation in the Cg
<jats:italic>ERG6</jats:italic>
gene may lead to a reduced susceptibility to polyenes and to a pseudohyphal growth due to the subsequent changes in sterol content of the plasma membrane.
</jats:p>