The evolution of fungal drug resistance: modulating the trajectory from genotype to phenotype.
Abstract
The emergence of drug resistance in pathogenic microorganisms provides an excellent example of microbial evolution that has had profound consequences for human health. The widespread use of antimicrobial agents in medicine and agriculture exerts strong selection for the evolution of drug resistance. Selection acts on the phenotypic consequences of resistance mutations, which are influenced by the genetic variation in particular genomes. Recent studies have revealed a mechanism by which the molecular chaperone heat shock protein 90 (Hsp90) can alter the relationship between genotype and phenotype in an environmentally contingent manner, thereby 'sculpting' the course of evolution. Harnessing Hsp90 holds great promise for treating life-threatening infectious diseases.
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The 1,3-β-D-glucan synthases are encoded by FKS1, FKS2, and FKS3 in S. cerevisiae, C. glabrata, and C. albicans, and require RHO1 for activity.
“The 1,3-β-D-glucan synthases are encoded by FKS1, FKS2, and FKS3 in S. cerevisiae, C. glabrata, and C. albicans, and require a regulatory subunit encoded by RHO1 for activity [3], [20], [32], [33].”
From Global Analysis of the Evolution and Mechanism of Echinocandin Resistance in Candida glabrata (2012) · cites this paper as [3]
The echinocandins target biosynthesis of 1,3-β-D-glucan.
“The echinocandins are the only novel class of antifungal drugs approved for clinical use in decades and target the biosynthesis of the key fungal cell wall component, 1,3-β-D-glucan [3], [20], [32].”
From Global Analysis of the Evolution and Mechanism of Echinocandin Resistance in Candida glabrata (2012) · cites this paper as [3]
Hsp90 stabilizes the catalytic subunit of calcineurin in both S. cerevisiae and C. albicans, thereby enabling calcineurin-dependent responses to drug-induced cellular stress.
“Hsp90 stabilizes the catalytic subunit of calcineurin in both S. cerevisiae and C. albicans [41], [91], thereby enabling calcineurin-dependent responses to drug-induced cellular stress [3], [92].”
From Global Analysis of the Evolution and Mechanism of Echinocandin Resistance in Candida glabrata (2012) · cites this paper as [3]
Hsp90 enables resistance to both azoles and echinocandins, in large part via calcineurin in C. albicans.
“Hsp90 enables resistance to both the azoles and echinocandins, in large part via the protein phosphatase calcineurin in C. albicans [3], [41], [44], [47].”
From Global Analysis of the Evolution and Mechanism of Echinocandin Resistance in Candida glabrata (2012) · cites this paper as [3]
The Hsp90-calcineurin axis is a crucial element governing stress adaptation processes in fungi.
“The heat shock protein 90 (Hsp90)-calcineurin axis is a crucial element governing stress adaptation processes in fungi (5).”
From Identification of a Key Lysine Residue in Heat Shock Protein 90 Required for Azole and Echinocandin Resistance in Aspergillus fumigatus (2014) · cites this paper as [5]
Hsp90 can enable the phenotypic effects of new mutations either by stabilizing mutant regulators or by stabilizing non-mutant regulators that mediate signalling required for adaptation.
“Second, Hsp90 can enable the phenotypic effects of new mutations either by stabilizing mutant regulators or by stabilizing non-mutant regulators that mediate signalling required for adaptation.”
From Fungal Hsp90: a biological transistor that tunes cellular outputs to thermal inputs (2012) · cites this paper as [135]
Hsp90's role as a potentiator for genetic variation has been observed in fungi as well as mammalian cancer cells.
“This role as a potentiator for genetic variation has been observed in fungi as well as mammalian cancer cells20,88,135,136.”
From Fungal Hsp90: a biological transistor that tunes cellular outputs to thermal inputs (2012) · cites this paper as [135]
There is increasing evidence of Hsp90's regulatory role in azole resistance development.
“there is increasing evidence of its regulatory role in azole resistance development.”
From Molecular and genetic basis of azole antifungal resistance in the opportunistic pathogenic fungus<i>Candida albicans</i> (2020) · cites this paper as [162]
Hsp90 potentiates the evolution of drug resistance traits, including some azole resistance mechanisms.
“has been shown to potentiate the evolution of drug resistance traits, including some azole resistance mechanisms.”
From Molecular and genetic basis of azole antifungal resistance in the opportunistic pathogenic fungus<i>Candida albicans</i> (2020) · cites this paper as [162]
Hsp90 is involved in the folding of a diverse set of client proteins and the regulation of signal transduction pathways.
“Hsp90 is involved in the folding of a diverse set of client proteins and the regulation of signal transduction pathways”
From Molecular and genetic basis of azole antifungal resistance in the opportunistic pathogenic fungus<i>Candida albicans</i> (2020) · cites this paper as [162]
In C. albicans, two major classes of efflux pumps modulate drug exportation: the ATP-binding cassette transporter superfamily (including CDR1 and CDR2) and the major facilitator class (including MDR1).
“In C. albicans, two major classes of efflux pumps modulate drug exportation: the ATP-binding cassette transporter superfamily (including CDR1 and CDR2) and the major facilitator class (including MDR1) (4, 33, 156).”
From <i>Candida albicans</i> Biofilms and Human Disease (2015) · cites this paper as [33]
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References 154 · Cited by 311
- Authors
- Cowen, L. E.
- Affiliations
- University of Toronto (CA)
- Corresponding author
- Cowen, Leah E.
- ORCID
- Cowen, Leah E.
- Venue
- Nature Reviews Microbiology
- Published
- 2008-03
- Volume
- 6
- Issue
- 3
- Pages
- 187-198
- ISSN
- 1740-1526 (ISSN-L)
- 1740-1534
- OpenAlex
- W1972736746
- Cited by
- 311
- References
- 154
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 11 · 2023: 13 · 2022: 10 · 2021: 18 · 2020: 27 · 2019: 19 · 2018: 14 · 2017: 21 · 2016: 26 · 2015: 16 · 2014: 26 · 2013: 19 · 2012: 24
- FWCI
- 1.31
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Reviews Microbiology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Keywords
- fungal drug resistance, HSP90, genotype-phenotype correlation, molecular chaperones, antimicrobial resistance, fungal pathogens, environmental selection, resistance mutations, microbial evolution, Hsp90 inhibitors
- MeSH terms
- Antifungal Agents, Biological Evolution, Fungi, Selection, Genetic, Genetic Variation, HSP90 Heat-Shock Proteins, Drug Resistance, Fungal
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