Cryptococcus neoformans Overcomes Stress of Azole Drugs by Formation of Disomy in Specific Multiple Chromosomes

Sionov, Edward; Lee, Hyeseung; Chang, Yun C.; Kwon-Chung, Kyung J.

doi:10.1371/journal.ppat.1000848

Cited by 479Fungal Infections and StudiesAntifungal resistance and susceptibilityFungal and yeast genetics research

Cryptococcus neoformans Overcomes Stress of Azole Drugs by Formation of Disomy in Specific Multiple Chromosomes

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Sionov, Edward, Lee, Hyeseung, Chang, Yun C., Kwon-Chung, Kyung J.·2010·PLoS Pathogens

DOI 10.1371/journal.ppat.1000848PMC PMC2848560

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Abstract

Cryptococcus neoformans is a haploid environmental organism and the major cause of fungal meningoencephalitis in AIDS patients. Fluconazole (FLC), a triazole, is widely used for the maintenance therapy of cryptococcosis. Heteroresistance to FLC, an adaptive mode of azole resistance, was associated with FLC therapy failure cases but the mechanism underlying the resistance was unknown. We used comparative genome hybridization and quantitative real-time PCR in order to show that C. neoformans adapts to high concentrations of FLC by duplication of multiple chromosomes. Formation of disomic chromosomes in response to FLC stress was observed in both serotype A and D strains. Strains that adapted to FLC concentrations higher than their minimal inhibitory concentration (MIC) contained disomies of chromosome 1 and stepwise exposure to even higher drug concentrations induced additional duplications of several other specific chromosomes. The number of disomic chromosomes in each resistant strain directly correlated with the concentration of FLC tolerated by each strain. Upon removal of the drug pressure, strains that had adapted to high concentrations of FLC returned to their original level of susceptibility by initially losing the extra copy of chromosome 1 followed by loss of the extra copies of the remaining disomic chromosomes. The duplication of chromosome 1 was closely associated with two of its resident genes: ERG11, the target of FLC and AFR1, the major transporter of azoles in C. neoformans. This adaptive mechanism in C. neoformans may play an important role in FLC therapy failure of cryptococcosis leading to relapse during azole maintenance therapy.

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If any of the ERG11, SEY1, GCS2 or GLO3 genes are relocated to chr3, then the frequency of chr3 disomy could increase.
“If any of the ERG11, SEY1, GCS2 or GLO3 genes are relocated to chr3, then the frequency of chr3 disomy could increase [143,144].”
From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [144]
The Results section ('ERG11 is important for chromosome 1 duplication under azole stress'; page unavailable) reports that strains with a single copy of ERG11 relocated to Chr3 duplicated Chr3 under fluconazole stress. Our copy does not establish that relocating SEY1, GCS2, or GLO3 would increase Chr3 disomy, so the claim's extension to those genes is unsupported by this source. (LLM, conf=0.88)
Experimental — accuracy not yet measured
In C. neoformans, heteroresistance can lead to resistant populations.
“For C. neoformans, a phenomenon referred to as heteroresistance can lead to resistant populations.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [71]
In C. neoformans heteroresistance, single cells give rise to progeny with heterogeneous resistant phenotypes, with a small but consistent subset of progeny highly resistant to azoles.
“Here, single cells give rise to progeny with heterogeneous resistant phenotypes, with a small but consistent subset of progeny highly resistant to the azoles.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [71]
C. neoformans heteroresistance allows populations to adapt to increasing concentrations of azoles in a stepwise manner, although susceptibility is typically restored after passage in the absence of drug.
“This phenomenon allows populations to adapt to increasing concentrations of the azoles in a stepwise manner, although susceptibility is typically restored after passage in the absence of drug.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [71]
In C. neoformans, heteroresistance is often acquired through formation of disomies, most prevalent being chromosome 1, which contains both ERG11 and the ABC transporter gene AFR1.
“In C. neoformans, heteroresistance is often acquired through the formation of disomies, the most prevalent being that of chromosome 1, which contains both ERG11 and the ABC transporter gene AFR171.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [71]

Large genomic rearrangements such as aneuploidies result in the concerted over- or under-expression of several genes.
“large genomic re-arrangements such as aneuploidies are good candidates because they result in the concerted over- or under-expression (depending on whether there is a gain or loss of chromosomes) of several genes”
From Evolutionary Emergence of Drug Resistance in Candida Opportunistic Pathogens (2018) · cites this paper as [126]
Aneuploidies are rather common, particularly under stress conditions.
“they are rather common, particularly under stress conditions [124,125,126]”
From Evolutionary Emergence of Drug Resistance in Candida Opportunistic Pathogens (2018) · cites this paper as [126]
Aneuploidies are well tolerated by cells.
“they are well tolerated by the cells”
From Evolutionary Emergence of Drug Resistance in Candida Opportunistic Pathogens (2018) · cites this paper as [126]
The traits of genomic plasticity and physiological adaptability can be inherited and are often transient, such that they are lost when the stress is removed.
“These traits can be inherited, and are often transient, such that they are lost when the stress is removed17,18.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [17]
Aneuploidy has been reported for chromosomes 6, 10, 11 and 14, although the specific genetic elements responsible for the selective advantage remain unclear.
“Aneuploidy has been reported for other chromosomes, including chromosomes 6, 10, 11 and 14, although the specific genetic elements responsible for the selective advantage remain unclear17,22,25,26.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [17]
Disomy of chromosome 1, which contains ERG11 and the predominant efflux pump gene AFR1, is the most common aneuploidy conferring azole heteroresistance.
“most commonly involving disomy of chromosome 1, which contains ERG11 and the predominant efflux pump gene AFR1 (ref.17).”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [17]
Heteroresistance primarily occurs through the formation of aneuploid cells, both in vitro and in vivo.
“Heteroresistance primarily occurs through the formation of aneuploid cells, both in vitro and in vivo17,22,24 (Fig. 1)”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [17]
Fluconazole heteroresistance occurs in C. neoformans via successive duplication of chromosomes 1, 4, 10, and 14 on increasing concentrations of fluconazole.
“Fluconazole heteroresistance occurs in C. neoformans via successive duplication of chromosomes 1, 4, 10, and 14 on increasing concentrations of fluconazole.”
From Mismatch Repair of DNA Replication Errors Contributes to Microevolution in the Pathogenic Fungus Cryptococcus neoformans (2017) · cites this paper as [10]
These disomic chromosomes allow the rapid emergence of fluconazole resistance; however, the disomic chromosomes are lost when fluconazole is removed, presumably due to reduced fitness as evidenced by reduced proliferation and virulence.
“These disomic chromosomes allow the rapid emergence of fluconazole resistance; however, the disomic chromosomes are lost when fluconazole is removed, presumably due to reduced fitness as evidenced by reduced proliferation and virulence (10).”
From Mismatch Repair of DNA Replication Errors Contributes to Microevolution in the Pathogenic Fungus Cryptococcus neoformans (2017) · cites this paper as [10]

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Authors: Sionov, E., Lee, H., Chang, Y. C., & Kwon-Chung, K. J.
Affiliations: National Institutes of Health (US)
Corresponding author: Kwon-Chung, Kyung J.
ORCID: Sionov, Edward
Chang, Yun C.
Kwon-Chung, Kyung J.
Venue: PLoS Pathogens
Publisher: Public Library of Science (PLoS)
Published: 2010-04-01
Volume: 6
Issue: 4
Pages: e1000848
ISSN: 1553-7366 (ISSN-L)
1553-7374
DOI: 10.1371/journal.ppat.1000848
PMC: PMC2848560
OpenAlex: W2028793515
Cited by: 479
References: 56
Citations by year: 2026: 33 · 2025: 38 · 2024: 24 · 2023: 32 · 2022: 36 · 2021: 40 · 2020: 36 · 2019: 36 · 2018: 26 · 2017: 29 · 2016: 24 · 2015: 26 · 2014: 29 · 2013: 31 · 2012: 23
FWCI: 16.06
Type: journal article
Language: en
Open access: gold
doi.org
Licence: public-domain
creativecommons.org/publicdomain/zero/1.0/ (unspecified)
Locations: PLoS Pathogens (publishedVersion, public-domain)
PubMed Central (publishedVersion, public-domain)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Figshare (submittedVersion, cc-by)
Funders: National Institutes of Health
National Institute of Allergy and Infectious Diseases
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, heteroresistance, chromosome duplication, adaptive drug resistance, ERG11, cryptococcosis, antifungal treatment failure
MeSH terms: Antifungal Agents, Azoles, Cell Separation, Cryptococcus neoformans, Flow Cytometry, Fluconazole, Chromosomes, Fungal, In Situ Hybridization, Reverse Transcriptase Polymerase Chain Reaction, Drug Resistance, Fungal, Comparative Genomic Hybridization

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Cryptococcus neoformans Overcomes Stress of Azole Drugs by Formation of Disomy in Specific Multiple Chromosomes

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