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Participation of the ABC Transporter CDR1 in Azole Resistance of Candida lusitaniae
Candida lusitaniae is an opportunistic pathogen in humans that causes infrequent but difficult-to-treat diseases. Antifungal drugs are used in the clinic to treat C. lusitaniae infections, however, this fungus can rapidly acquire antifungal resistance to all known antifungal drugs (multidrug resista...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8467326/ https://www.ncbi.nlm.nih.gov/pubmed/34575798 http://dx.doi.org/10.3390/jof7090760 |
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author | Borgeat, Valentin Brandalise, Danielle Grenouillet, Frédéric Sanglard, Dominique |
author_facet | Borgeat, Valentin Brandalise, Danielle Grenouillet, Frédéric Sanglard, Dominique |
author_sort | Borgeat, Valentin |
collection | PubMed |
description | Candida lusitaniae is an opportunistic pathogen in humans that causes infrequent but difficult-to-treat diseases. Antifungal drugs are used in the clinic to treat C. lusitaniae infections, however, this fungus can rapidly acquire antifungal resistance to all known antifungal drugs (multidrug resistance). C. lusitaniae acquires azole resistance by gain-of-function (GOF) mutations in the transcriptional regulator MRR1. MRR1 controls the expression of a major facilitator transporter (MFS7) that is important for fluconazole resistance. Here, we addressed the role of the ATP Binding Cassette (ABC) transporter CDR1 as additional mediator of azole resistance in C. lusitaniae. CDR1 expression in isolates with GOF MRR1 mutations was higher compared to wild types, which suggests that CDR1 is an additional (direct or indirect) target of MRR1. CDR1 deletion in the azole-resistant isolate P3 (V688G GOF) revealed that MICs of long-tailed azoles, itraconazole and posaconazole, were decreased compared to P3, which is consistent with the role of this ABC transporter in the efflux of these azoles. Fluconazole MIC was only decreased when CDR1 was deleted in the background of an mfs7Δ mutant from P3, which underpins the dominant role of MFS7 in the resistance of the short-tailed azole fluconazole. With R6G efflux readout as Cdr1 efflux capacity, our data showed that R6G efflux was increased in P3 compared to an azole-susceptible wild type parent, and diminished to background levels in mutant strains lacking CDR1. Milbemycin oxim A3, a known inhibitor of fungal ABC transporters, mimicked efflux phenotypes of cdr1Δ mutants. We therefore provided evidence that CDR1 is an additional mediator of azole resistance in C. lusitaniae, and that CDR1 regulation is dependent on MRR1 and associated GOF mutations. |
format | Online Article Text |
id | pubmed-8467326 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-84673262021-09-27 Participation of the ABC Transporter CDR1 in Azole Resistance of Candida lusitaniae Borgeat, Valentin Brandalise, Danielle Grenouillet, Frédéric Sanglard, Dominique J Fungi (Basel) Article Candida lusitaniae is an opportunistic pathogen in humans that causes infrequent but difficult-to-treat diseases. Antifungal drugs are used in the clinic to treat C. lusitaniae infections, however, this fungus can rapidly acquire antifungal resistance to all known antifungal drugs (multidrug resistance). C. lusitaniae acquires azole resistance by gain-of-function (GOF) mutations in the transcriptional regulator MRR1. MRR1 controls the expression of a major facilitator transporter (MFS7) that is important for fluconazole resistance. Here, we addressed the role of the ATP Binding Cassette (ABC) transporter CDR1 as additional mediator of azole resistance in C. lusitaniae. CDR1 expression in isolates with GOF MRR1 mutations was higher compared to wild types, which suggests that CDR1 is an additional (direct or indirect) target of MRR1. CDR1 deletion in the azole-resistant isolate P3 (V688G GOF) revealed that MICs of long-tailed azoles, itraconazole and posaconazole, were decreased compared to P3, which is consistent with the role of this ABC transporter in the efflux of these azoles. Fluconazole MIC was only decreased when CDR1 was deleted in the background of an mfs7Δ mutant from P3, which underpins the dominant role of MFS7 in the resistance of the short-tailed azole fluconazole. With R6G efflux readout as Cdr1 efflux capacity, our data showed that R6G efflux was increased in P3 compared to an azole-susceptible wild type parent, and diminished to background levels in mutant strains lacking CDR1. Milbemycin oxim A3, a known inhibitor of fungal ABC transporters, mimicked efflux phenotypes of cdr1Δ mutants. We therefore provided evidence that CDR1 is an additional mediator of azole resistance in C. lusitaniae, and that CDR1 regulation is dependent on MRR1 and associated GOF mutations. MDPI 2021-09-15 /pmc/articles/PMC8467326/ /pubmed/34575798 http://dx.doi.org/10.3390/jof7090760 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Borgeat, Valentin Brandalise, Danielle Grenouillet, Frédéric Sanglard, Dominique Participation of the ABC Transporter CDR1 in Azole Resistance of Candida lusitaniae |
title | Participation of the ABC Transporter CDR1 in Azole Resistance of Candida lusitaniae |
title_full | Participation of the ABC Transporter CDR1 in Azole Resistance of Candida lusitaniae |
title_fullStr | Participation of the ABC Transporter CDR1 in Azole Resistance of Candida lusitaniae |
title_full_unstemmed | Participation of the ABC Transporter CDR1 in Azole Resistance of Candida lusitaniae |
title_short | Participation of the ABC Transporter CDR1 in Azole Resistance of Candida lusitaniae |
title_sort | participation of the abc transporter cdr1 in azole resistance of candida lusitaniae |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8467326/ https://www.ncbi.nlm.nih.gov/pubmed/34575798 http://dx.doi.org/10.3390/jof7090760 |
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