Identification and characterization of a Cryptococcus neoformans ATP binding cassette (ABC) transporter‐encoding gene, CnAFR1, involved in the resistance to fluconazole

Posteraro, Brunella; Sanguinetti, Maurizio; Sanglard, Dominique; La Sorda, Marilena; Boccia, Stefania; Romano, Lucio; Morace, Giulia; Fadda, Giovanni

doi:10.1046/j.1365-2958.2003.03281.x

Cited by 143Fungal Infections and StudiesAntifungal resistance and susceptibilityFungal and yeast genetics research

Identification and characterization of a Cryptococcus neoformans ATP binding cassette (ABC) transporter‐encoding gene, CnAFR1, involved in the resistance to fluconazole

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Posteraro, Brunella, Sanguinetti, Maurizio, Sanglard, Dominique, La Sorda, Marilena, Boccia, Stefania, Romano, Lucio, Morace, Giulia, Fadda, Giovanni·2003·Molecular Microbiology

DOI 10.1046/j.1365-2958.2003.03281.x

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Abstract

Summary: Resistance to fluconazole is a possible event during prolonged suppressive drug therapy for cryptococ‐cal meningitis, the most frequently encountered life‐threatening manifestation of cryptococcosis. The knowledge of this resistance at the molecular level is important for management of cryptococcosis. In order to identify genes involved in azole resistance in Cryptococcus neoformans, a cDNA subtraction library technique was chosen as a strategy. First, a fluconazole‐resistant mutant BPY22.17 was obtained from a susceptible clinical isolate BPY22 by in vitro exposure to the drug. Then, a subtractive hybridization procedure was used to compare gene expression between the obtained strains. We identified a cDNA overexpressed in the fluconazole‐resistant strain BPY22.17 that was used as a probe to isolate the entire gene in a C. neoformans genomic library. Sequence analysis of this gene identified an ATP Binding Cassette (ABC) transporter‐encoding gene called C. neoformans AntiFungal Resistance 1 (CnAFR1). Disruption of CnAFR1 gene in the resistant isolate (BPY22.17) resulted in an enhanced susceptibility of the knock‐out mutant cnafr1 against fluconazole, whereas reintroduction of the gene in cnafr1 resulted in restoration of the resistance phenotype, thus confirming that CnAFR1 is involved in fluconazole resistance of C. neoformans. Our findings therefore reveal that an active drug efflux mechanism can be involved in the development of azole resistance in this important human pathogen.

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Overexpression of multidrug efflux transporters mediates azole resistance in other fungal pathogens, with the major players being ABC transporters Afr1 and AtrF for C. neoformans and A. fumigatus, respectively.
“Overexpression of multidrug efflux transporters also mediates azole resistance in other fungal pathogens, with the major players being the ABC transporters Afr1 and AtrF for C. neoformans and A. fumigatus, respectively60,61.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [61]

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Authors: Posteraro, B., Sanguinetti, M., Sanglard, D., La Sorda, M., Boccia, S., Romano, L., Morace, G., & Fadda, G.
Affiliations: Università Cattolica del Sacro Cuore (IT)
Centre Hospitalier Universitaire Vaudois (CH)
University of Milan (IT)
Corresponding author: Fadda, Giovanni
ORCID: Posteraro, Brunella
Sanguinetti, Maurizio
Sanglard, Dominique
Boccia, Stefania
Morace, Giulia
Venue: Molecular Microbiology
Publisher: Wiley
Published: 2003-01
Volume: 47
Issue: 2
Pages: 357-371
ISSN: 0950-382X (ISSN-L)
1365-2958
DOI: 10.1046/j.1365-2958.2003.03281.x
OpenAlex: W1595790960
Cited by: 143
References: 84
Citations by year: 2026: 4 · 2025: 2 · 2024: 1 · 2023: 7 · 2022: 7 · 2021: 4 · 2020: 3 · 2019: 7 · 2018: 6 · 2017: 9 · 2016: 7 · 2015: 5 · 2014: 11 · 2013: 5 · 2012: 6
FWCI: 4.41
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor, 9 d)
Locations: Molecular Microbiology (publishedVersion)
PubMed (publishedVersion)
IRIS (submittedVersion)
SERVAL (Université de Lausanne) (submittedVersion)
Funders: Istituto Superiore di Sanità
Topics: Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
Keywords: Cryptococcus neoformans, fluconazole resistance, azole resistance, ABC transporters, drug efflux, cryptococcal meningitis, cryptococcosis, gene disruption, gene overexpression
MeSH terms: Amino Acid Sequence, Antifungal Agents, Cloning, Molecular, Cryptococcus neoformans, Fungal Proteins, Humans, Microbial Sensitivity Tests, Molecular Sequence Data, Nucleic Acid Hybridization, Gene Library, Fluconazole, Sequence Alignment, Gene Deletion, ATP-Binding Cassette Transporters, Drug Resistance, Fungal

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Identification and characterization of a Cryptococcus neoformans ATP binding cassette (ABC) transporter‐encoding gene, CnAFR1, involved in the resistance to fluconazole

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