An A643T mutation in the transcription factor Upc2p causes constitutive ERG11 upregulation and increased fluconazole resistance in Candida albicans

Clemens J. Heilmann, Sabrina Schneider, Katherine S. Barker, Phillip Rogers, Joachim Morschhäuser

Research output: Contribution to journalArticle

72 Citations (Scopus)

Abstract

The zinc cluster transcription factor Upc2p mediates upregulation of ergosterol biosynthesis genes in response to ergosterol depletion in the fungal pathogen Candida albicans. One mechanism of acquired resistance to the antifungal drug fluconazole, which inhibits ergosterol biosynthesis, is constitutively increased expression of the ERG11 gene encoding the drug target enzyme. A G648D mutation in Upc2p has recently been shown to cause hyperactivity of the transcription factor, resulting in overexpression of ergosterol biosynthesis genes and increased fluconazole resistance. In order to investigate if gain-of-function mutations in Upc2p are a common mechanism of ERG11 upregulation and fluconazole resistance, we sequenced the UPC2 alleles of four ERG11-overexpressing, fluconazole-resistant C. albicans isolates and matched susceptible isolates from the same patients. In three of the isolate pairs, no differences in the UPC2 alleles were found, suggesting that mechanisms other than Upc2p mutations can cause ERG11 overexpression. One resistant isolate had become homozygous for a UPC2 allele containing a G1927A substitution that caused an alanine-to-threonine exchange at amino acid position 643 of Upc2p. Replacement of one of the endogenous UPC2 alleles in a fluconazole-susceptible strain by the UPC2A643T allele resulted in ERG11 overexpression and increased fluconazole resistance, which was further elevated when the A643T mutation was also introduced into the second UPC2 allele. These results further establish gain-of-function mutations in UPC2, which can be followed by loss of heterozygosity for the mutated allele, as a mechanism of ERG11 overexpression and increased fluconazole resistance in C. albicans, but other mechanisms of ERG11 upregulation also exist.

Original languageEnglish (US)
Pages (from-to)353-359
Number of pages7
JournalAntimicrobial Agents and Chemotherapy
Volume54
Issue number1
DOIs
StatePublished - Jan 1 2010

Fingerprint

Fluconazole
Candida albicans
Transcription Factors
Up-Regulation
Alleles
Ergosterol
Mutation
Fungal Drug Resistance
Loss of Heterozygosity
Threonine
Alanine
Genes
Zinc
Gene Expression
Amino Acids
Enzymes
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Infectious Diseases
  • Pharmacology (medical)
  • Pharmacology

Cite this

An A643T mutation in the transcription factor Upc2p causes constitutive ERG11 upregulation and increased fluconazole resistance in Candida albicans. / Heilmann, Clemens J.; Schneider, Sabrina; Barker, Katherine S.; Rogers, Phillip; Morschhäuser, Joachim.

In: Antimicrobial Agents and Chemotherapy, Vol. 54, No. 1, 01.01.2010, p. 353-359.

Research output: Contribution to journalArticle

Heilmann, Clemens J. ; Schneider, Sabrina ; Barker, Katherine S. ; Rogers, Phillip ; Morschhäuser, Joachim. / An A643T mutation in the transcription factor Upc2p causes constitutive ERG11 upregulation and increased fluconazole resistance in Candida albicans. In: Antimicrobial Agents and Chemotherapy. 2010 ; Vol. 54, No. 1. pp. 353-359.
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