Journal article
Contributions of both ATP-Binding Cassette Transporter and Cyp51A Proteins Are Essential for Azole Resistance in Aspergillus fumigatus
Antimicrobial agents and chemotherapy, Vol.61(5), e02748-16
05/01/2017
DOI: 10.1128/AAC.02748-16
PMCID: PMC5404575
PMID: 28264842
Abstract
While azole drugs targeting the biosynthesis of ergosterol are effective antifungal agents, their extensive use has led to the development of resistant organisms. Infections involving azole-resistant forms of the filamentous fungus
Aspergillus fumigatus
are often associated with genetic changes in the
cyp51A
gene encoding the lanosterol α14 demethylase target enzyme. Both a sequence duplication in the
cyp51A
promoter (TR34) and a substitution mutation in the coding sequence (L98H) are required for the full expression of azole resistance. A mechanism commonly observed in pathogenic yeast such as
Candida albicans
involves gain-of-function mutations in transcriptional regulatory proteins that induce expression of genes encoding ATP-binding cassette (ABC) transporters. We and others have found that an ABC transporter protein called Cdr1B (here referred to as AbcG1) is required for wild-type azole resistance in
A. fumigatus
. Here, we test the genetic relationship between the TR34 L98H allele of
cyp51A
and an
abcG1
null mutation. Loss of AbcG1 from a TR34 L98H
cyp51A
-containing strain caused a large decrease in the azole resistance of the resulting double-mutant strain. We also generated antibodies that enabled the detection of both the wild-type and L98H forms of the Cyp51A protein. The introduction of the L98H lesion into the
cyp51A
gene led to a decreased production of immunoreactive enzyme, suggesting that this mutant protein is unstable. Our data confirm the importance of AbcG1 function during azole resistance even in a strongly drug-resistant background.
Details
- Title: Subtitle
- Contributions of both ATP-Binding Cassette Transporter and Cyp51A Proteins Are Essential for Azole Resistance in Aspergillus fumigatus
- Creators
- Sanjoy Paul - Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USADaniel Diekema - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAW. Scott Moye-Rowley - Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
- Resource Type
- Journal article
- Publication Details
- Antimicrobial agents and chemotherapy, Vol.61(5), e02748-16
- Publisher
- American Society for Microbiology; 1752 N St., N.W., Washington, DC
- DOI
- 10.1128/AAC.02748-16
- PMID
- 28264842
- PMCID
- PMC5404575
- ISSN
- 0066-4804
- eISSN
- 1098-6596
- Grant note
- GM49825 / HHS | National Institutes of Health (NIH) AI113748 / HHS | National Institutes of Health (NIH)
- Alternative title
- A. fumigatus Azole Resistance Determinants
- Language
- English
- Date published
- 05/01/2017
- Academic Unit
- Molecular Physiology and Biophysics; Infectious Diseases; Pathology; Internal Medicine
- Record Identifier
- 9984003199802771
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