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Cited by 304Antifungal resistance and susceptibilityFungal and yeast genetics researchFungal Plant Pathogen Control

Molecular mechanisms governing antifungal drug resistance

Open access
Lee, Yunjin, Robbins, Nicole, Cowen, Leah E.·2023·npj Antimicrobials and Resistance
DOI 10.1038/s44259-023-00007-2PMC PMC11057204
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Abstract

Fungal pathogens are a severe public health problem. The leading causative agents of systemic fungal infections include species from the Candida , Cryptococcus , and Aspergillus genera. As opportunistic pathogens, these fungi are generally harmless in healthy hosts; however, they can cause significant morbidity and mortality in immunocompromised patients. Despite the profound impact of pathogenic fungi on global human health, the current antifungal armamentarium is limited to only three major classes of drugs, all of which face complications, including host toxicity, unfavourable pharmacokinetics, or limited spectrum of activity. Further exacerbating this issue is the growing prevalence of antifungal-resistant infections and the emergence of multidrug-resistant pathogens. In this review, we discuss the diverse strategies employed by leading fungal pathogens to evolve antifungal resistance, including drug target alterations, enhanced drug efflux, and induction of cellular stress response pathways. Such mechanisms of resistance occur through diverse genetic alterations, including point mutations, aneuploidy formation, and epigenetic changes given the significant plasticity observed in many fungal genomes. Additionally, we highlight recent literature surrounding the mechanisms governing resistance in emerging multidrug-resistant pathogens including Candida auris and Candida glabrata . Advancing our knowledge of the molecular mechanisms by which fungi adapt to the challenge of antifungal exposure is imperative for designing therapeutic strategies to tackle the emerging threat of antifungal resistance.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes molecular mechanisms by which major fungal pathogens evolve antifungal resistance, including drug target alteration/overexpression, enhanced efflux, genomic plasticity, cellular stress responses, and epigenetic/RNA-based regulation. It highlights resistance in emerging multidrug-resistant pathogens such as *Candida auris* and *Candida glabrata* and discusses therapeutic strategies to counter resistance.

Key findings

  • Fungal pathogens cause an estimated 1.5 million deaths annually; invasive candidiasis mortality exceeds 40% despite treatment, cryptococcal infection causes an estimated 112,000 deaths per year, and invasive aspergillosis has 50% mortality even with diagnosis and intervention, approaching 100% if untreated.
  • Resistance mechanisms include drug target alteration or overexpression, enhanced drug efflux, genomic plasticity (aneuploidy, copy number variations, loss of heterozygosity, horizontal gene transfer), cellular stress responses (Hsp90, calcineurin, PKC-MAPK, TOR, CK1), and epigenetic regulation (histone acetylation/methylation, chromatin remodeling, RNAi epimutations).
  • Azole resistance involves over 140 distinct Erg11 amino acid substitutions in *C. albicans*, ERG11 mutations in *C. auris* (including F444L), cyp51A promoter duplications with TR34/L98H and TR46/Y121F/T289A in *A. fumigatus*, and efflux pump upregulation via TAC1, MRR1, and PDR1.
  • Echinocandin resistance frequently involves FKS1/FKS2 mutations; in one experimental evolution study, all 121 anidulafungin-resistant *C. glabrata* lineages harbored nonsynonymous FKS mutations, with 22% outside well-characterized hot-spot regions. Polyene resistance remains rare due to severe fitness trade-offs.

Methods

  • Narrative review synthesizing published literature on antifungal resistance mechanisms in *Candida*, *Cryptococcus*, *Aspergillus*, *C. auris*, *C. glabrata*, and *Mucor circinelloides*.
  • No primary experimental data, systematic search strategy, inclusion/exclusion criteria, or quantitative synthesis are described in the text.

Limitations

  • Stated: future work is needed to characterize genes contributing to resistance in aneuploidies beyond i(5L), test horizontal gene transfer under host-relevant conditions, determine whether RNAi epimutation-mediated resistance generalizes to other fungal pathogens, and develop improved genetic tools for essential genes in *C. neoformans*.
  • Evident: as a narrative review, it lacks a systematic search strategy, formal quality assessment, and quantitative synthesis; conclusions rely on cited literature rather than primary experimental validation.

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

Integrity signals

Registry

Crossref · 10.1038/s44259-023-00007-2

Cites

116 of 116 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 149 cited sources checked · 0 supported · 0 flagged

  • Interpretationnone given

    Drug target alteration is a common mechanism leading to acquired antifungal resistance.

    “Drug target alteration is a common mechanism leading to acquired antifungal resistance.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Mutations in ERG11 contribute to reduced azole susceptibility in C. auris.

    “Mutations in ERG11 also contribute to reduced azole susceptibility in the emerging fungal pathogen C. auris12–15, with a recent study highlighting a previously unreported substitution in Erg11 (F444L) identified in azole-resistant clade IV clinical isolates that has not been previously described in other reports15.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [12] Chowdhary, A. et al. A multicentre study of antifungal susceptibility patterns among 350 Candida auris isolates (2009–17) in India: role of the ERG11 and FKS1 genes in azole and echinocandin resistance. J. Antimicrob. Chemother. 73, 891–899 (2018). source

      Not checked in the free run.

    • cites [13] Healey, K. R. et al. Limited ERG11 mutations identified in isolates of Candida auris directly contribute to reduced azole susceptibility. Antimicrob. Agents. Chemother. 62, e01427–18 (2018). source

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    • cites [14] Rybak, J. M. et al. Delineation of the direct contribution of Candida auris ERG11 mutations to clinical triazole resistance. Microbiol. Spectr. 9, e0158521 (2021). source

      Not checked in the free run.

    • cites [15] Li, J. et al. Novel ERG11 and TAC1b mutations associated with azole resistance in Candida auris. Antimicrob. Agents. Chemother. 65, e02663–20 (2021). source

      Not checked in the free run.

  • Premisecitation

    A previously unreported Erg11 substitution F444L was identified in azole-resistant clade IV clinical isolates of C. auris.

    “with a recent study highlighting a previously unreported substitution in Erg11 (F444L) identified in azole-resistant clade IV clinical isolates that has not been previously described in other reports15.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Li, J. et al. Novel ERG11 and TAC1b mutations associated with azole resistance in Candida auris. Antimicrob. Agents. Chemother. 65, e02663–20 (2021). source

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  • Premisenone given

    For azoles, resistance involves alterations in genes encoding the azole drug target 14-α-demethylase (ERG11 in yeast and cyp51 in moulds).

    “For azoles, resistance involves alterations in genes encoding the azole drug target 14-α-demethylase (ERG11 in yeast and cyp51 in moulds).”
    Quote in the paperSubstantial claim
  • Premisecitation

    Additional regulators of cyp51A expression that contribute to azole resistance in A. fumigatus include the fungal-specific transcription factors AtrR and SltA.

    “Additional regulators of cyp51A expression that contribute to azole resistance in A. fumigatus include the fungal-specific transcription factors AtrR and SltA30–32.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [30] Hagiwara, D. et al. A novel Zn2-Cys6 transcription factor AtrR plays a key role in an azole resistance mechanism of Aspergillus fumigatus by co-regulating cyp51A and cdr1B expressions. PLoS. Pathog. 13, e1006096 (2017). source

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    • cites [31] Paul, S. et al. AtrR is an essential determinant of azole resistance in Aspergillus fumigatus. mBio. 10, e02563–18 (2019). source

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    • cites [32] Du, W. et al. The C2H2 transcription factor SltA contributes to azole resistance by coregulating the expression of the drug target Erg11A and the drug efflux pump Mdr1 in Aspergillus fumigatus. Antimicrob. Agents. Chemother. 65, e01839–20 (2021). source

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  • May combine two claims. 28
  • Classified as probably not a substantial claim. 3

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    Premisecitation

    Structural analysis of C. albicans Erg11 demonstrated that some substitutions involve residues exposed in the active-site cavity and directly affect azole binding, while others occur on the proximal surface and may indirectly contribute to azole resistance.

    “Structural analysis of C. albicans Erg11 demonstrated that while some substitutions involve residues that are exposed in the active-site cavity (directly affecting azole binding), others occur on the proximal surface of the enzyme and may indirectly contribute to azole resistance (for example, by influencing interactions with cytochrome P450 reductase)11.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Hargrove, T. Y. et al. Structural analyses of Candida albicans sterol 14α-demethylase complexed with azole drugs address the molecular basis of azole-mediated inhibition of fungal sterol biosynthesis. J. Biol. Chem. 292, 6728–6743 (2017). source

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  • May combine two claims.

    Premisecitation

    In clinical isolates of C. albicans, over 140 distinct Erg11 amino acid substitutions have been reported, with most clustering into three hot spot regions.

    “In clinical isolates of C. albicans, over 140 distinct Erg11 amino acid substitutions have been reported in the literature, with most clustering into three hot spot regions9,10.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] Morio, F., Loge, C., Besse, B., Hennequin, C. & le Pape, P. Screening for amino acid substitutions in the Candida albicans Erg11 protein of azole-susceptible and azole-resistant clinical isolates: new substitutions and a review of the literature. Diagn. Microbiol. Infect. Dis. 66, 373–384 (2010). source

      Not checked in the free run.

    • cites [10] Marichal, P. et al. Contribution of mutations in the cytochrome P450 14alpha-demethylase (Erg11p, Cyp51p) to azole resistance in Candida albicans. Microbiology (Reading). 145, 2701–2713 (1999). source

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    Premisecitation

    In a mouse model of invasive pulmonary aspergillosis, infection with an echinocandin-resistant strain of A. fumigatus was less lethal than with the echinocandin-susceptible strain, with reduced lung fungal burden and significantly longer survival time.

    “In a mouse model of invasive pulmonary aspergillosis, infection with an echinocandin-resistant strain of A. fumigatus was less lethal when compared with the echinocandin-susceptible strain, as demonstrated by reduced lung fungal burden and significantly longer survival time44.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Lewis, R. E., Liao, G., Hou, J., Prince, R. A. & Kontoyiannis, D. P. Comparative in vivo dose-dependent activity of caspofungin and anidulafungin against echinocandin-susceptible and -resistant Aspergillus fumigatus. J. Antimicrob. Chemother. 66, 1324–1331 (2011). source

      Not checked in the free run.

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    Premisecitation

    In C. albicans, FKS1 is an essential gene encoding a catalytic subunit of the 1,3-β-glucan synthase complex, whereas in C. glabrata, FKS1 and FKS2 are functionally redundant for viability.

    “In C. albicans, FKS1 is an essential gene encoding a catalytic subunit of the 1,3-β-glucan synthase complex, whereas in C. glabrata, FKS1 and FKS2 are functionally redundant for viability35.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Katiyar, S. K. et al. Fks1 and Fks2 are functionally redundant but differentially regulated in Candida glabrata: implications for echinocandin resistance. Antimicrob. Agents. Chemother. 56, 6304–6309 (2012). source

      Not checked in the free run.

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    Interpretationcitation

    For A. fumigatus, echinocandin resistance in clinical settings is extremely rare, likely due to the fitness cost of FKS1 mutations in vivo.

    “For A. fumigatus, echinocandin resistance in clinical settings is extremely rare, likely due to the fitness cost of FKS1 mutations in vivo44.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Lewis, R. E., Liao, G., Hou, J., Prince, R. A. & Kontoyiannis, D. P. Comparative in vivo dose-dependent activity of caspofungin and anidulafungin against echinocandin-susceptible and -resistant Aspergillus fumigatus. J. Antimicrob. Chemother. 66, 1324–1331 (2011). source

      Not checked in the free run.

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    Premisecitation

    In experimental evolution with C. glabrata, all 121 anidulafungin-resistant lineages harboured non-synonymous mutations in FKS genes, with mutations preferentially occurring in FKS2 as opposed to FKS1.

    “A recent study leveraging experimental evolution with C. glabrata generated 121 anidulafungin-resistant lineages. Intriguingly, all 121 strains harboured non-synonymous mutations in FKS genes, with mutations preferentially occurring in FKS2 as opposed to FKS136.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] Ksiezopolska, E. et al. Narrow mutational signatures drive acquisition of multidrug resistance in the fungal pathogen Candida glabrata. Curr. Biol. 31, 5314–5326.e10 (2021). source

      Not checked in the free run.

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    Premisecitation

    Analysis of mutant Fks1 S643P revealed conformational changes that lead to shifts of nearby bound lipids, suggesting a potential additional mechanism for drug resistance through alterations in cellular physiology.

    “Further analysis of the structure of mutant Fks1 (S643P), which affects lipid binding, revealed conformational changes that lead to shifts of nearby bound lipids, suggesting a potential additional mechanism for drug resistance that does not simply result in a decrease in drug binding to its target but that is a result of alterations in cellular physiology43.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [43] Hu, X. et al. Structural and mechanistic insights into fungal β-1,3-glucan synthase. FKS1. Nature. 616, 190–198 (2023). source

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    Premisecitation

    The Upc2 LBD exhibits ligand-dependent conformational switching and mutations of the glycine-rich loop interfere with ligand binding via steric clashes, resulting in constitutive activation.

    “The Upc2 LBD exhibits ligand-dependent conformational switching and mutations of the glycine-rich loop interfere with ligand binding via steric clashes, resulting in constitutive activation26.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Tan, L. et al. Structural basis for activation of fungal sterol receptor Upc2 and azole resistance. Nat. Chem. Biol. 18, 1253–1262 (2022). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Duplications in the cyp51A gene promoter coupled with TR34/L98H and TR46/Y121F/T289A substitutions are becoming widespread in the environment associated with azole use in agriculture and are also isolated from hospital patients without previous antifungal exposure.

    “Alarmingly, duplications in the cyp51A gene promoter coupled with specific amino acid substitutions, TR34/L98H and TR46/Y121F/T289A, are becoming widespread in the environment associated with azole use in agriculture, while also isolated from hospital patients without previous exposure to antifungal drugs19–22.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [19] Sewell, T. R. et al. Nonrandom distribution of azole resistance across the global population of Aspergillus fumigatus. mBio. 10, e00392–19 (2019). source

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    • cites [20] Schoustra, S. E. et al. Environmental hotspots for azole resistance selection of Aspergillus fumigatus, the Netherlands. Emerg. Infect. Dis. 25, 1347–1353 (2019). source

      Not checked in the free run.

    • cites [21] Hurst, S. F., Berkow, E. L., Stevenson, K. L., Litvintseva, A. P. & Lockhart, S. R. Isolation of azole-resistant Aspergillus fumigatus from the environment in the south-eastern USA. J. Antimicrob. Chemother. 72, 2443–2446 (2017). source

      Not checked in the free run.

    • cites [22] Alvarez-Moreno, C. et al. Azole-resistant Aspergillus fumigatus harboring TR34/L98H, TR46/Y121F/T289A and TR53 mutations related to flower fields in Colombia. Sci. Rep. 7, 45631 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Echinocandins retained some activity against the A. fumigatus FKS1 mutant strain in vivo, albeit a lack of appreciable activity in vitro.

    “Notably, echinocandins retained some activity against the A. fumigatus FKS1 mutant strain in vivo, albeit a lack of appreciable activity in vitro, which may further contribute to the rare clinical occurrence of echinocandin resistance in this species44.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Lewis, R. E., Liao, G., Hou, J., Prince, R. A. & Kontoyiannis, D. P. Comparative in vivo dose-dependent activity of caspofungin and anidulafungin against echinocandin-susceptible and -resistant Aspergillus fumigatus. J. Antimicrob. Chemother. 66, 1324–1331 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Cellular stress response pathways are critical in enabling pathogen survival in response to diverse environmental perturbations and play integral roles in alleviating antifungal-induced stress.

    “Cellular stress response pathways are critical in enabling pathogen survival in response to diverse environmental perturbations and, as such, play integral roles in alleviating antifungal-induced stress (Fig. 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In evolution of 144 C. albicans lineages with various fluconazole concentrations, lineages evolved with drug concentrations close to their MIC50 had a propensity to rapidly evolve an increased MIC50 and acquired distinct segmental aneuploidies and CNVs.

    “Through the evolution of 144 C. albicans lineages in the presence of various concentrations of fluconazole, the authors observed that those lineages evolved with drug concentrations close to their MIC50 (the minimum inhibitory concentration of drug that reduces growth by 50%) had a propensity to rapidly evolve an increased MIC50 and acquired distinct segmental aneuploidies and CNVs69.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [69] Todd, R. T. et al. Antifungal drug concentration impacts the spectrum of adaptive mutations in Candida albicans. Mol. Biol. Evol. 40, msad009 (2023). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Fungal pathogens possess remarkable genomic plasticity that promotes survival in different environments, with significant implications for the evolution of antifungal drug resistance.

    “Thus, fungal pathogens possess remarkable genomic plasticity that promotes survival in different environments, with significant implications for the evolution of antifungal drug resistance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Upc2A also regulates CDR1 expression and extensive overlap exists between the regulatory networks mediated by Upc2A and Pdr1 in C. glabrata.

    “Recently, it was demonstrated that the zinc cluster transcription factor Upc2A also regulates CDR1 expression and that extensive overlap exists between the regulatory networks mediated by Upc2A and Pdr1 in C. glabrata27,59.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [27] Vu, B. G., Stamnes, M. A., Li, Y., Rogers, P. D. & Moye-Rowley, W. S. The Candida glabrata Upc2A transcription factor is a global regulator of antifungal drug resistance pathways. PLoS. Genet. 17, e1009582 (2021). source

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    • cites [59] Vu, B. G., Thomas, G. H. & Moye-Rowley, W. S. Evidence that ergosterol biosynthesis modulates activity of the Pdr1 transcription factor in Candida glabrata. mBio. 10, e00934–19 (2019). source

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    Premisecitation

    Gain-of-function mutations in TAC1 result in constitutive overexpression of both CDR1 and CDR2, while activating mutations in MRR1 are responsible for upregulation of MDR1.

    “Specifically, gain-of-function mutations in the transcriptional activator gene, TAC1, result in constitutive overexpression of both CDR1 and CDR2, while activating mutations in MRR1 are responsible for the upregulation of MDR152,53.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [52] Coste, A. et al. A mutation in Tac1p, a transcription factor regulating CDR1 and CDR2, is coupled with loss of heterozygosity at chromosome 5 to mediate antifungal resistance in Candida albicans. Genetics. 172, 2139–2156 (2006). source

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    • cites [53] Dunkel, N., Blaß, J., Rogers, P. D. & Morschhäuser, J. Mutations in the multi-drug resistance regulator MRR1, followed by loss of heterozygosity, are the main cause of MDR1 overexpression in fluconazole-resistant Candida albicans strains. Mol. Microbiol. 69, 827–840 (2008). source

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  • May combine two claims.

    Premisecitation

    Exposure to hydroxyurea or tunicamycin selects for trisomy of chromosome 2 in C. albicans, which also enables tolerance to caspofungin.

    “Recent work in C. albicans demonstrated that exposure to the cancer chemotherapeutic hydroxyurea, or the ER stress-inducing agent tunicamycin selects for trisomy of chromosome 2, which also enables tolerance to the echinocandin caspofungin66,67.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [66] Yang, F. et al. Aneuploidy enables cross-adaptation to unrelated drugs. Mol. Biol. Evol. 36, 1768–1782 (2019). source

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    • cites [67] Yang, F. et al. Tunicamycin potentiates antifungal drug tolerance via aneuploidy in Candida albicans. mBio. 12, e0227221 (2021). source

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    Premisecitation

    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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [71] Sionov, E., Lee, H., Chang, Y. C. & Kwon-Chung, K. J. Cryptococcus neoformans overcomes stress of azole drugs by formation of disomy in specific multiple chromosomes. PLoS. Pathog. 6, e1000848 (2010). source

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    Premisecitation

    A. fumigatus can undergo both chromosomal and plasmid-mediated HGT of voriconazole resistance via a mutated resistance-conferring allele of cyp51A, with plasmid-mediated HGT detected under conditions of voriconazole stress alone.

    “Notably, A. fumigatus can undergo both chromosomal and plasmid-mediated HGT of voriconazole resistance (via a mutated resistance-conferring allele of cyp51A), with the latter being detected under conditions of voriconazole stress alone, implicating HGT as a potential route to antifungal resistance in this pathogen72.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [72] Morogovsky, A., Handelman, M., Abou Kandil, A., Shadkchan, Y. & Osherov, N. Horizontal gene transfer of triazole resistance in Aspergillus fumigatus. Microbiol. Spectr. 10, e0111222 (2022). source

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    Premisecitation

    These complex CNVs are flanked by distinct long inverted repeat sequences, found across the genome, and often contain genes associated with drug resistance.

    “These complex CNVs are flanked by distinct long inverted repeat sequences and are found across the genome, often containing genes associated with drug resistance68.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [68] Todd, R. T. & Selmecki, A. Expandable and reversible copy number amplification drives rapid adaptation to antifungal drugs. Elife. 9, e58349 (2020). source

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    Premisecitation

    Extensive copy number variations (CNVs) amplify large genomic regions and drive rapid acquisition of azole resistance in C. albicans.

    “Another significant source of genomic diversity that drives the rapid acquisition of azole resistance in C. albicans involves extensive copy number variations (CNVs), which amplify large genomic regions68.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [68] Todd, R. T. & Selmecki, A. Expandable and reversible copy number amplification drives rapid adaptation to antifungal drugs. Elife. 9, e58349 (2020). source

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  • May combine two claims.

    Interpretationcitation

    Changes in whole chromosome copy number can occur in response to diverse stress conditions and enable tolerance to antifungals despite no prior exposure.

    “Strikingly, changes in whole chromosome copy number can occur in response to diverse stress conditions and enable tolerance to antifungals despite no prior exposure.”
    Quote in the paperSubstantial claim

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    Premisecitation

    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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [71] Sionov, E., Lee, H., Chang, Y. C. & Kwon-Chung, K. J. Cryptococcus neoformans overcomes stress of azole drugs by formation of disomy in specific multiple chromosomes. PLoS. Pathog. 6, e1000848 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In S. cerevisiae, Rlm1 is the major regulator of cell wall integrity and its transcriptional output includes genes involved in cell wall biogenesis, while SBF is a cell cycle transcription factor that regulates transcription of cell wall-related genes including FKS2 under conditions of cell wall stress.

    “In S. cerevisiae, Rlm1 is the major regulator of cell wall integrity and its transcriptional output includes genes involved in cell wall biogenesis, while SBF is a cell cycle transcription factor that regulates the transcription of cell wall-related genes including FKS2 under conditions of cell wall stress84.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [84] Levin, D. E. Cell wall integrity signaling in Saccharomyces cerevisiae. Microbiol. Mol. Biol. Rev. 69, 262–291 (2005). source

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

    Interpretationreasoning

    There is potential crosstalk between Hrr25 and Pkc1 signalling in regulating drug-induced stress responses.

    “Given that SBF is a well-characterized downstream effector of the PKC-MAPK cascade, this highlights the potential crosstalk between Hrr25 and Pkc1 signalling in regulating drug-induced stress responses78,89”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [78] LaFayette, S. L. et al. PKC signaling regulates drug resistance of the fungal pathogen Candida albicans via circuitry comprised of Mkc1, Calcineurin, and Hsp90. PLoS. Pathog. 6, e1001069 (2010). source

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    • cites [89] Lee, Y., Liston, S. D., Lee, D., Robbins, N. & Cowen, L. E. Functional analysis of the Candida albicans kinome reveals Hrr25 as a regulator of antifungal susceptibility. iScience. 25, 104432 (2022). source

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  • May combine two claims.

    Premisecitation

    PKC also regulates membrane stress responses in C. albicans and this process is largely dependent on Rlm1.

    “As discussed previously, PKC also regulates membrane stress responses in C. albicans and this process is largely dependent on Rlm178.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [78] LaFayette, S. L. et al. PKC signaling regulates drug resistance of the fungal pathogen Candida albicans via circuitry comprised of Mkc1, Calcineurin, and Hsp90. PLoS. Pathog. 6, e1001069 (2010). source

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  • Classified as probably not a substantial claim.

    Premisecitation

    SBF is a well-characterized downstream effector of the PKC-MAPK cascade.

    “Given that SBF is a well-characterized downstream effector of the PKC-MAPK cascade, this highlights the potential crosstalk between Hrr25 and Pkc1 signalling in regulating drug-induced stress responses78,89”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [78] LaFayette, S. L. et al. PKC signaling regulates drug resistance of the fungal pathogen Candida albicans via circuitry comprised of Mkc1, Calcineurin, and Hsp90. PLoS. Pathog. 6, e1001069 (2010). source

      Not checked in the free run.

    • cites [89] Lee, Y., Liston, S. D., Lee, D., Robbins, N. & Cowen, L. E. Functional analysis of the Candida albicans kinome reveals Hrr25 as a regulator of antifungal susceptibility. iScience. 25, 104432 (2022). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mutations in ERG3 can be acquired upon echinocandin exposure in vitro and confer cross-resistance to fluconazole in C. glabrata.

    “While the role of ERG3 mutations in azole resistance has been less evident in C. glabrata, recent work demonstrated that mutations in ERG3 can be acquired upon echinocandin exposure in vitro and confer cross-resistance to fluconazole36.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] Ksiezopolska, E. et al. Narrow mutational signatures drive acquisition of multidrug resistance in the fungal pathogen Candida glabrata. Curr. Biol. 31, 5314–5326.e10 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Beauvericin potentiates azole activity via both inhibition of TOR and multidrug efflux.

    “The natural product beauvericin, which potentiates azole activity via both inhibition of TOR and multidrug efflux, is effective against diverse fungal pathogens including C. albicans, C. neoformans, and A. fumigatus87.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [87] Shekhar-Guturja, T. et al. Dual action antifungal small molecule modulates multidrug efflux and TOR signaling. Nat. Chem. Biol. 12, 867–875 (2016). source

      Not checked in the free run.

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

    Interpretationnone given

    Continued efforts to advance our mechanistic understanding of antifungal resistance will support the development of therapeutic strategies to combat invasive fungal infections.

    “Continued efforts to advance our mechanistic understanding of antifungal resistance will undoubtedly support the development of therapeutic strategies to combat invasive fungal infections.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Antifungal resistance is a significant clinical challenge.

  • May combine two claims.

    Interpretationcitation

    Histone modifications are important not only in the maintenance of azole resistance but also in the acquisition of azole resistance.

    “Notably, in C. glabrata, inhibition of Gcn5 minimized the emergence of PDR1 gain-of-function alleles in evolution experiments with fluconazole, suggesting the importance of histone modifications not only in the maintenance of azole resistance but also in the acquisition of azole resistance95.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [95] Usher, J. & Haynes, K. Attenuating the emergence of anti-fungal drug resistance by harnessing synthetic lethal interactions in a model organism. PLoS. Genet. 15, e1008259 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Significant challenges with the delivery of antifungal RNAs include fungal cell permeability and susceptibility to degradation by RNases in the host environment.

    “While significant challenges with the delivery of antifungal RNAs include fungal cell permeability and susceptibility to degradation by RNases in the host environment, several promising approaches are underway in related systems, which may be applied to the treatment of fungal infections106.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [106] Bruch, A., Kelani, A. A. & Blango, M. G. RNA-based therapeutics to treat human fungal infections. Trends. Microbiol. 30, 411–420 (2022). source

      Not checked in the free run.

31 of 31

  • The paper relies on this without support.

    The current antifungal armamentarium is limited to only three major classes of drugs.

    “Despite the profound impact of pathogenic fungi on global human health, the current antifungal armamentarium is limited to only three major classes of drugs, all of which face complications, including host toxicity, unfavourable pharmacokinetics, or limited spectrum of activity.”
    “Indeed, only three major classes of antifungal drugs exist in clinical practice to treat invasive fungal diseases (Fig. 1).”

  • The paper relies on this without support.

    The close evolutionary relationship between fungi and humans limits the number of fungal-specific targets that can be exploited for drug development.

    “The generation of antifungals has been slow-paced in part due to the close evolutionary relationship between fungi and humans, limiting the number of fungal-specific targets that can be exploited for drug development.”

  • The paper relies on this without support.

    Antifungal resistance is a significant clinical challenge.

    “Our scarce antifungal arsenal, combined with the rising prevalence of drug-resistant fungal pathogens, represents a significant clinical challenge for the present and future.”

  • The paper relies on this without support.

    RNAi is ubiquitous.

    “Given the ubiquitous nature of RNAi, there has been growing interest in RNA-based therapeutics for the treatment of fungal infections, particularly in the management of crop diseases105.”
4 of 4

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Authors
Lee, Y., Robbins, N., & Cowen, L. E.
Affiliations
University of Toronto (CA)
Corresponding author
Cowen, Leah E.
ORCID
Venue
npj Antimicrobials and Resistance
Publisher
Springer Science and Business Media LLC
Published
2023-07-17
Volume
1
Issue
1
Pages
5-5
ISSN
2731-8745 (ISSN-L)
DOI
10.1038/s44259-023-00007-2
PMC
PMC11057204
OpenAlex
W4384559034
Semantic Scholar
719f4924a71facb56cf1d5a7dc143f3ea37a5a43
Cited by
304
References
116
Citations by year
2026: 113 · 2025: 122 · 2024: 64 · 2023: 5
FWCI
14.42
Type
journal article
Language
en
Open access
Licence
Locations
  • npj Antimicrobials and Resistance (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Gouvernement du Canada|Canadian Institutes of Health Research (FDN-154288)
  • Division of Intramural Research, National Institute of Allergy and Infectious Diseases (R01AI1654661)
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 › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
Keywords
antifungal resistance, fungal pathogens, Candida auris, Candida glabrata, Cryptococcus, Aspergillus, multidrug resistance, drug efflux, drug target alterations, stress response pathways, aneuploidy, epigenetic modifications, immunocompromised patients, systemic fungal infection

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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