Role of ATP-binding-cassette transporter genes in high-frequency acquisition of resistance to azole antifungals in Candida glabrata

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Serval ID
serval:BIB_AA0F0FCC122A
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Role of ATP-binding-cassette transporter genes in high-frequency acquisition of resistance to azole antifungals in Candida glabrata
Journal
Antimicrobial Agents and Chemotherapy
Author(s)
Sanglard  D., Ischer  F., Bille  J.
ISSN
0066-4804 (Print)
Publication state
Published
Issued date
04/2001
Volume
45
Number
4
Pages
1174-83
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Apr
Abstract
Candida glabrata has been often isolated from AIDS patients with oropharyngeal candidiasis treated with azole antifungal agents, especially fluconazole. We recently showed that the ATP-binding-cassette (ABC) transporter gene CgCDR1 was upregulated in C. glabrata clinical isolates resistant to azole antifungal agents (D. Sanglard, F. Ischer, D. Calabrese, P. A. Majcherczyk, and J. Bille, Antimicrob. Agents Chemother. 43:2753-2765, 1999). Deletion of CgCDR1 in C. glabrata rendered the null mutant hypersusceptible to azole derivatives and showed the importance of this gene in mediating azole resistance. We observed that wild-type C. glabrata exposed to fluconazole in a medium containing the drug at 50 microg/ml developed resistance to this agent and other azoles at a surprisingly high frequency (2 x 10(-4) to 4 x 10(-4)). We show here that this high-frequency azole resistance (HFAR) acquired in vitro was due, at least in part, to the upregulation of CgCDR1. The CgCDR1 deletion mutant DSY1041 could still develop HFAR but in a medium containing fluconazole at 5 microg/ml. In the HFAR strain derived from DSY1041, a distinct ABC transporter gene similar to CgCDR1, called CgCDR2, was upregulated. This gene was slightly expressed in clinical isolates but was upregulated in strains with the HFAR phenotype. Deletion of both CgCDR1 and CgCDR2 suppressed the development of HFAR in a medium containing fluconazole at 5 microg/ml, showing that both genes are important mediators of resistance to azole derivatives in C. glabrata. We also show here that the HFAR phenomenon was linked to the loss of mitochondria in C. glabrata. Mitochondrial loss could be obtained by treatment with ethidium bromide and resulted in acquisition of resistance to azole derivatives without previous exposure to these agents. Azole resistance obtained in vitro by HFAR or by agents stimulating mitochondrial loss was at least linked to the upregulation of both CgCDR1 and CgCDR2.
Keywords
ATP-Binding Cassette Transporters/biosynthesis/genetics/*physiology Antifungal Agents/*pharmacology Candida/*drug effects/genetics/metabolism Cell Division/drug effects Dose-Response Relationship, Drug Drug Resistance, Microbial Fluconazole/*pharmacology Gene Deletion *Genes, Fungal Microbial Sensitivity Tests Mitochondria/drug effects RNA, Messenger/biosynthesis Up-Regulation
Pubmed
Web of science
Open Access
Yes
Create date
25/01/2008 14:40
Last modification date
20/08/2019 15:14
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