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Journal article
Upregulation of ERG Genes in Candida Species by Azoles and Other Sterol Biosynthesis Inhibitors
Antimicrobial agents and chemotherapy, v 44(10), pp 2693-2700
01 Oct 2000
PMCID: PMC90137
PMID: 10991846
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Abstract
Infections due to
Candida albicans
are usually treated with azole antifungals such as fluconazole, but treatment failure is not uncommon especially in immunocompromised individuals. Relatedly, in vitro studies demonstrate that azoles are nonfungicidal, with continued growth at strain-dependent rates even at high azole concentrations. We hypothesized that upregulation of
ERG11
, which encodes the azole target enzyme lanosterol demethylase, contributes to this azole tolerance in
Candida
species. RNA analysis revealed that
ERG11
expression in
C. albicans
is maximal during logarithmic-phase growth and decreases as the cells approach stationary phase. Incubation with fluconazole, however, resulted in a two- to fivefold increase in
ERG11
RNA levels within 2 to 3 h, and this increase was followed by resumption of culture growth.
ERG11
upregulation also occurred following treatment with other azoles (itraconazole, ketoconazole, clotrimazole, and miconazole) and was not dependent on the specific medium or pH. Within 1 h of drug removal
ERG11
upregulation was reversed. Azole-dependent upregulation was not limited to
ERG11
: five of five
ERG
genes tested whose products function upstream and downstream of lanosterol demethylase in the sterol biosynthetic pathway were also upregulated. Similarly,
ERG11
upregulation occurred following treatment of
C. albicans
cultures with terbinafine and fenpropimorph, which target other enzymes in the pathway. These data suggest a common mechanism for global
ERG
upregulation, e.g., in response to ergosterol depletion. Finally, azole-dependent
ERG11
upregulation was demonstrated in three additional
Candida
species (
C. tropicalis
,
C. glabrata
, and
C. krusei
), indicating a conserved response to sterol biosynthesis inhibitors in opportunistic yeasts.
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Details
- Title
- Upregulation of ERG Genes in Candida Species by Azoles and Other Sterol Biosynthesis Inhibitors
- Creators
- Karl W. Henry - Hahnemann University HospitalJoseph T. Nickels - Hahnemann University HospitalThomas D. Edlind - Department of Microbiology and Immunology#N#1#N# and
- Publication Details
- Antimicrobial agents and chemotherapy, v 44(10), pp 2693-2700
- Publisher
- American Society for Microbiology
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000089402300018
- Scopus ID
- 2-s2.0-0033807662
- Other Identifier
- 991019168156804721
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- Web of Science research areas
- Microbiology
- Pharmacology & Pharmacy