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Cited by 94Antifungal resistance and susceptibilityFungal and yeast genetics researchYeasts and Rust Fungi Studies

Genetic Drivers of Multidrug Resistance in Candida glabrata

Open access
Healey, Kelley R., Jimenez Ortigosa, Cristina, Shor, Erika, Perlin, David S.·2016·Frontiers in Microbiology
DOI 10.3389/fmicb.2016.01995PMC PMC5156712
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Abstract

Both the incidence of invasive fungal infections and rates of multidrug resistance associated with fungal pathogen Candida glabrata have increased in recent years. In this perspective, we will discuss the mechanisms underlying the capacity of C. glabrata to rapidly develop resistance to multiple drug classes, including triazoles and echinocandins. We will focus on the extensive genetic diversity among clinical isolates of C. glabrata, which likely enables this yeast to survive multiple stressors, such as immune pressure and antifungal exposure. In particular, over half of C. glabrata clinical strains collected from U.S. and non-U.S. sites have mutations in the DNA mismatch repair gene MSH2, leading to a partial mutator phenotype and increased frequencies of drug-resistant mutants in vitro. Furthermore, recent studies and data presented here document extensive chromosomal rearrangements among C. glabrata strains, resulting in a large number of distinct karyotypes within a single species. By analyzing clonal, serial isolates derived from individual patients treated with antifungal drugs, we were able to document chromosomal changes occurring in C. glabrata in vivo during the course of antifungal treatment. Interestingly, we also show that both MSH2 genotypes and chromosomal patterns cluster consistently into specific strain types, indicating that C. glabrata has a complex population structure where genomic variants arise, perhaps during the process of adaptation to environmental changes, and persist over time.

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Written from the paper’s full text.

TL;DR

This perspective argues that *Candida glabrata*’s high genetic diversity—driven by prevalent *MSH2* mismatch-repair mutations and extensive chromosomal rearrangements—promotes rapid multidrug resistance. New analyses of serial clinical isolates show karyotypic changes during antifungal treatment and clustering of *MSH2* genotypes and chromosomal patterns by strain type.

Key findings

  • Over half (55%) of *C. glabrata* isolates recovered from patients contain mutations in the mismatch repair gene *MSH2*; these mutations pre-date antifungal resistance, are associated with higher in vitro emergence of resistance, and *msh2Δ* increases breakthrough antifungal treatment in a mouse GI colonization model. *MSH2* genotypes show geographic clustering: 75 of 76 strains with *msh2*-E231G/L269F or *msh2*-P208S/N890I came from U.S. centers, while 95 of 125 *msh2*-V239L/A942T or *msh2*-V239L alleles came from non-U.S. centers.
  • Multidrug resistance is emerging: 11% of fluconazole-resistant *C. glabrata* isolates from 2006–2010 were also echinocandin resistant, versus none from 2001–2004; a 2010 Duke Hospital study found 14% of fluconazole-resistant isolates also resistant to at least one echinocandin and 3.5% of all *C. glabrata* isolates MDR; a cancer hospital survey from 2005–2013 reported nearly 7% MDR. Fluconazole resistance occurs in approximately 20–30% of U.S. *C. glabrata* strains versus less than 5% of *C. albicans* strains, and echinocandin resistance in *C. glabrata* increased from 3 to 12%.
  • Chromosomal architecture is highly plastic: PFGE of three serial isolate pairs showed unique karyotypes, and even sequential isolates from the same patient had distinct chromosomal bands, particularly among larger chromosomes. MLST has identified over 80 sequence types, and typing of 48 clinical strains found 6 strains with novel MLST alleles or configurations; strains of the same sequence type shared similar chromosomal patterns, and different *MSH2* alleles were characteristic of distinct sequence types/clades.

Methods

  • Design: a perspective that summarizes published studies and presents new data from the Perlin laboratory historic strain collection; isolates were previously obtained without patient identifiers.
  • New data: serial bloodstream *C. glabrata* isolates from three patients before and after echinocandin therapy were analyzed by MLST to verify lineage, CLSI broth microdilution MICs for fluconazole and echinocandins, sequencing of *FKS1*, *FKS2*, *PDR1*, and *MSH2*, and PFGE karyotyping. MLST was also performed on 48 clinical strains.
  • Main analysis: descriptive comparison of MICs, mutations, sequence types, and karyotypes; no formal statistical model is stated.

Limitations

  • Stated: the reasons for the steep increase in *C. glabrata* infections and for the greatest rise in echinocandin resistance remain largely unclear; whether other fungi use similar MMR-mediated diversity remains to be addressed; high karyotypic variability prevents reference-based genome assembly, requiring de novo approaches; continued global tracking of strain types is needed.
  • Evident from the text: the new data are small and descriptive—three serial isolate pairs and preliminary MLST of 48 strains, with some data not shown—and no statistical testing or causal inference is reported.
  • Evident from the text: as a perspective rather than a systematic review, the paper selectively summarizes prior literature and does not provide a comprehensive or quantitative synthesis.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3389/fmicb.2016.01995

Cites

77 of 77 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 58 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Deletion of MSH2 causes elevated propensity to breakthrough antifungal treatment in a mouse model of gastrointestinal colonization.

    “deletion of MSH2 causes elevated propensity to breakthrough antifungal treatment in a mouse model of gastrointestinal (GI) colonization”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Healey et al., 2016 source

      Not checked in the free run.

  • Findingown data

    The overwhelming majority of strains (75 of 76) that exhibit msh2-E231G/L269F or msh2-P208S/N890I were recovered at U.S. based medical centers.

    “The overwhelming majority of strains (75 of 76) that exhibit msh2-E231G/L269F or msh2-P208S/N890I were recovered at U.S. based medical centers.”
    Quote in the paperSubstantial claim
  • Findingnone given

    C. glabrata clinical isolates have highly variable chromosomal profiles.

    “As described above, C. glabrata clinical isolates have highly variable chromosomal profiles.”
    Quote in the paperSubstantial claim
  • Findingcitation

    Complete loss of MMR function (msh2Δ) impacts fitness of C. glabrata in the host.

    “we have demonstrated that complete loss of MMR function (msh2Δ) impacts fitness of C. glabrata in the host”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Healey et al., 2016 source

      Not checked in the free run.

  • Findingown data

    Analysis of serial clinical isolates demonstrated that msh2 mutations pre-date the emergence of antifungal resistance.

    “analysis of serial clinical isolates demonstrated that msh2 mutations pre-date the emergence of antifungal resistance”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Healey et al., 2016 source

      Not checked in the free run.

  • May combine two claims. 20
  • Classified as probably not a substantial claim. 11

  • May combine two claims.

    Findingown data

    Strains exhibiting one of the aforementioned msh2 mutations lead to only partial loss-of-function and may not suffer from the extremely high mutation rate and fitness defect observed with msh2Δ.

    “strains exhibiting one of the aforementioned msh2 mutations lead to only partial loss-of-function (data not shown) and may not suffer from the extremely high mutation rate and fitness defect observed with msh2Δ”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Strains containing either msh2-V239L/A942T or msh2-V239L were identified in both U.S. and non-U.S. centers, although these genotypes were predominant (95 of 125) among the msh2 mutant alleles identified from the non-U.S. centers.

    “Strains containing either msh2-V239L/A942T or msh2-V239L were identified in both U.S. and non-U.S. (Switzerland, Qatar, and India) centers, although these genotypes were predominant (95 of 125) among the msh2 mutant alleles identified from the non-U.S. centers.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Nucleotide polymorphisms and chromosomal rearrangements vary widely in C. glabrata yet group reliably into strain types.

    “We show that nucleotide polymorphisms and chromosomal rearrangements vary widely in C. glabrata yet group reliably into strain types.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    The prevalence of ST16, which carries an msh2 mutation and may therefore acquire drug resistance at elevated rates, increased.

    “One noteworthy change is the increased prevalence of ST16, which carries an msh2 mutation and may therefore acquire drug resistance at elevated rates.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Strains isolated from the same patient were more similar to each other than strains isolated from different patients, but sequential isolates obtained from the same individual had distinct chromosomal bands, particularly among the larger chromosomes.

    “While strains isolated from the same patient were more similar to each other than strains isolated from different patients, even sequential isolates obtained from the same individual had distinct chromosomal bands, particularly among the larger chromosomes (Figure 1B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In each serial pair, the first isolate was echinocandin sensitive, while the second isolate had acquired echinocandin resistance and an fks mutation.

    “in each case the first isolate was echinocandin sensitive, while the second isolate had acquired echinocandin resistance and an fks mutation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A MLST scheme based on six different loci has thus far identified over 80 different C. glabrata sequence types.

    “A MLST scheme based on six different loci has thus far identified over 80 different C. glabrata sequence types (STs, or clades) (Dodgson et al., 2003)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Dodgson et al., 2003

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    The geographical differences in MSH2 genotypes are most likely a result of population and/or treatment differences.

    “These geographical differences are most likely a result of population and/or treatment differences”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A CDC/SENTRY study found that none of the fluconazole-resistant C. glabrata isolates from 2001 to 2004 demonstrated echinocandin resistance, while 11% of fluconazole-resistant isolates from 2006 to 2010 were also resistant to an echinocandin.

    “A CDC/SENTRY Antimicrobial Surveillance Program study found that while none of the fluconazole-resistant C. glabrata isolates from 2001 to 2004 demonstrated echinocandin resistance, 11% of fluconazole-resistant isolates from 2006 to 2010 were also resistant to an echinocandin (Pfaller et al., 2012).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Pfaller et al., 2012 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The most frequent genome rearrangements identified in C. glabrata were translocations of chromosomal arms and inter-chromosomal duplications, but formation of novel chromosomes was also reported.

    “the most frequent genome rearrangements identified were translocations of chromosomal arms and inter-chromosomal duplications, but formation of novel chromosomes was also reported (Muller et al., 2009; Polakova et al., 2009).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Muller et al., 2009 source

      Not checked in the free run.

    • cites Polakova et al., 2009 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The distribution of C. glabrata STs varies both by geography and over time.

    “the distribution of C. glabrata STs varies both by geography and over time (Dodgson et al., 2003; Lott et al., 2010).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Dodgson et al., 2003

      Not checked in the free run.

    • cites Lott et al., 2010

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    MMR and DSBR mutants, but not BER or NER, lead to increased appearance of fluconazole-resistant colonies in C. albicans.

    “One study investigated the involvement of DNA repair mechanisms in drug resistance in C. albicans and demonstrated that mutants of MMR and DSBR, but not BER or NER, lead to increased appearance of fluconazole-resistant colonies (Legrand et al., 2007, 2008).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Legrand et al., 2007, 2008

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    C. glabrata readily develops cross-resistance to azoles, including fluconazole, itraconazole, voriconazole and posaconazole, which is often associated with upregulation of ABC transporters CDR1 and SNQ2.

    “C. glabrata readily develops cross-resistance to azoles, including fluconazole, itraconazole, voriconazole and posaconazole, which is often associated with upregulation of ATP-binding cassette (ABC) transporters, such as CDR1 and SNQ2, that effectively pump the drugs out of the yeast cell”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Sanglard et al., 1999, 2001

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Izumikawa et al., 2003 source

      Not checked in the free run.

    • cites Torelli et al., 2008 source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    All strains were subjected to MLST analysis to verify that each pair originated from the same lineage; both strains from each pair were of the same strain type.

    “All strains were subjected to multi-locus sequence typing (MLST) analysis (Dodgson et al., 2003) to verify that each pair originated from the same lineage; indeed, both strains from each pair were of the same strain type (Figure 1A).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Dodgson et al., 2003

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisenone given

    Upon exposure to environmental stresses, fungi activate stress responses to mitigate harmful effects and avoid death.

    “Upon exposure to environmental stresses, such as temperature, ionic, oxidative, and osmolarity changes, and/or drug pressure, fungi activate stress responses to mitigate the harmful effects and avoid death.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A survey of C. glabrata isolates from a cancer hospital between 2005 and 2013 reported nearly 7% as MDR.

    “a survey of C. glabrata isolates obtained from a cancer hospital between 2005 and 2013 reported nearly 7% as MDR (Farmakiotis et al., 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Farmakiotis et al., 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A Duke Hospital study in 2010 found that 14% of fluconazole-resistant isolates also exhibited resistance to at least one echinocandin and that 3.5% of all C. glabrata isolates were MDR.

    “Another study, performed at Duke Hospital in 2010, found that 14% of fluconazole-resistant isolates also exhibited resistance to at least one echinocandin and that 3.5% of all C. glabrata isolates were MDR (Alexander et al., 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Alexander et al., 2013 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Targeting the CWI pathway through deletion of PKC1 or activated MAP kinases induces echinocandin hypersensitivity, while increased activation of the pathway reduces susceptibility of C. glabrata to echinocandins.

    “Targeting the CWI pathway through deletion of PKC1 or activated MAP kinases (e.g., CgSLT2) induces echinocandin hypersensitivity; while conversely, an increased activation of the pathway, such as through over-expression of CgSLT2, reduces susceptibility (increases tolerance) of C. glabrata to echinocandins (Cota et al., 2008; Miyazaki et al., 2010a; Schwarzmuller et al., 2014).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Cota et al., 2008 source

      Not checked in the free run.

    • cites Miyazaki et al., 2010a

      Not checked in the free run.

    • cites Schwarzmuller et al., 2014 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The mechanisms discussed allow strains of C. glabrata to create genetically diverse populations within the human host and improve the yeast's chances of surviving multiple stressors, including antifungal treatment.

    “We propose that these mechanisms allow strains of C. glabrata to create genetically diverse populations within the human host and improve the yeast's chances of surviving multiple stressors, including antifungal treatment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The majority of MDR C. glabrata strains have acquired resistance to triazole and echinocandin class antifungals, with rare isolates demonstrating resistance to amphotericin B.

    “the majority of MDR C. glabrata strains have acquired resistance to triazole and echinocandin class antifungals, with rare isolates demonstrating resistance to amphotericin B (Farmakiotis et al., 2014; Cho et al., 2015).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Farmakiotis et al., 2014 source

      Not checked in the free run.

    • cites Cho et al., 2015

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Defects in DNA repair may underlie the emergence of drug-resistant variants in fungal pathogens such as C. glabrata.

    “Thus, defects in DNA repair may also underlie the emergence of drug-resistant variants in fungal pathogens such as C. glabrata.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Approximately 20-30% of C. glabrata strains, but less than 5% of C. albicans strains, exhibit fluconazole resistance in the U.S.

    “Approximately 20–30% of C. glabrata strains, but less than 5% of C. albicans strains, exhibit fluconazole resistance in the U.S. (Castanheira et al., 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Castanheira et al., 2014

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The cell wall integrity pathway is of particular importance upon echinocandin exposure and regulates glucan synthesis through Rho1 and cell wall repair.

    “Of particular importance upon echinocandin exposure is the cell wall integrity (CWI) pathway, which regulates glucan synthesis through Rho1 and cell wall repair (Levin, 2005).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Levin, 2005 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Tolerance mechanisms may prime cells, particularly C. glabrata, to better survive adverse conditions in vivo and better equip fungi to survive antifungal pressure.

    “Tolerance mechanisms may “prime” cells, particularly C. glabrata, to better survive adverse conditions in vivo and, in turn, better equip fungi to survive antifungal pressure.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Development of tolerance to fluconazole treatment at the population level may be one consequence of heteroresistance, which may allow the yeast to adapt and buy time until beneficial, stable mutations develop.

    “Development of tolerance to fluconazole treatment at the population level may be one consequence of heteroresistance, which in turn, may allow the yeast to adapt and “buy time” until beneficial, stable mutations develop.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    C. glabrata can tolerate a high degree of genome rearrangement and thrive under these circumstances, perhaps through acquisition of gain-of-fitness mutations.

    “It appears that, in contrast to many organisms, C. glabrata can tolerate such a high degree of genome rearrangement and thrive under these circumstances, perhaps through acquisition of gain-of-fitness mutations.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    There is a high prevalence in the global C. glabrata population of mutator phenotypes mediated by mutations in MSH2.

    “Maximizing genetic diversity, a hallmark of C. glabrata, is most apparent by the high prevalence in the global population of mutator phenotypes mediated by mutations in MSH2.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Histone deacetylase inhibitors act synergistically with antifungals.

    “histone deacetylase inhibitors act synergistically with antifungals (Garnaud et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Garnaud et al., 2016

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationnone given

    Yeast are exposed to additional pressures in vivo that may induce some kind of transient heterotolerance to the echinocandins that is not necessarily measurable in vitro.

    “However, yeast are exposed to additional pressures in vivo that may induce some kind of transient heterotolerance to the echinocandins that is not necessarily measurable in vitro.”
    Quote in the paperNot a substantial claim
29 of 29

  • The paper relies on this without support.

    The haploid genome of C. glabrata contributes to the observed increases in drug resistance rates.

    “Many groups, including ours, have attributed the observed increases in drug resistance rates to the haploid genome of C. glabrata. While this is most likely a factor, our recent studies have suggested that other prominent biological factors may contribute more profoundly to resistance emergence.”
1 of 1

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Research works printed but not linked: 1

  1. CLSI, 2012, Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved Standard 3rd Edn.

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Authors
Healey, K. R., Jimenez Ortigosa, C., Shor, E., & Perlin, D. S.
Affiliations
Rutgers Health (US)
Corresponding author
Healey, Kelley R.
ORCID
Venue
Frontiers in Microbiology
Publisher
Frontiers Media SA
Published
2016-12-15
Volume
7
Pages
1995-1995
ISSN
1664-302X (ISSN-L)
DOI
10.3389/fmicb.2016.01995
PMC
PMC5156712
OpenAlex
W2564635582
Semantic Scholar
ca13a51a922fc3c2cf7a26cfb00a5ce7d2429007
Cited by
93
References
77
Citations by year
2026: 4 · 2025: 11 · 2024: 7 · 2023: 4 · 2022: 10 · 2021: 10 · 2020: 12 · 2019: 14 · 2018: 13 · 2017: 8
FWCI
10.78
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Microbiology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (AI109025)
  • Arnold and Mabel Beckman Foundation
  • Astellas Pharma US
Topics
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Yeasts and Rust Fungi Studies
Keywords
Candida glabrata, multidrug resistance, antifungal resistance, triazole resistance, echinocandin resistance, MSH2, DNA mismatch repair, mutator phenotype, chromosomal rearrangements, karyotype diversity, population structure, invasive fungal infections, clinical isolates, clonal isolates

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