Expandable and reversible copy number amplification drives rapid adaptation to antifungal drugs

Todd, Robert T.; Selmecki, Anna

doi:10.7554/elife.58349

Cited by 108 publications

(153 citation statements)

References 188 publications

(274 reference statements)

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“…Interestingly, a recent study revealed that the copy number of CRZ1 was correlated with the occurrence of FCL tolerance in C. albicans isolates exposed to FLC. Assuming that CRZ1 gene copy number may be correlated with increased expression, this study corroborates with our observations ( Todd and Selmecki, 2020 ). How CRZ1 overexpression mediates azole tolerance is still unknown.…”

Section: Discussionsupporting

confidence: 92%

Identification and Characterization of Mediators of Fluconazole Tolerance in Candida albicans

Delarze¹,

Brandt²,

Trachsel³

et al. 2020

Front. Microbiol.

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Candida albicans is an important human pathogen and a major concern in intensive care units around the world. C. albicans infections are associated with a high mortality despite the use of antifungal treatments. One of the causes of therapeutic failures is the acquisition of antifungal resistance by mutations in the C. albicans genome. Fluconazole (FLC) is one of the most widely used antifungal and mechanisms of FLC resistance occurring by mutations have been extensively investigated. However, some clinical isolates are known to be able to survive at high FLC concentrations without acquiring resistance mutations, a phenotype known as tolerance. Mechanisms behind FLC tolerance are not well studied, mainly due to the lack of a proper way to identify and quantify tolerance in clinical isolates. We proposed here culture conditions to investigate FLC tolerance as well as an easy and efficient method to identity and quantify tolerance to FLC. The screening of C. albicans strain collections revealed that FLC tolerance is pH- and strain-dependent, suggesting the involvement of multiple mechanisms. Here, we addressed the identification of FLC tolerance mediators in C. albicans by an overexpression strategy focusing on 572 C. albicans genes. This strategy led to the identification of two transcription factors, CRZ1 and GZF3 . CRZ1 is a C2H2-type transcription factor that is part of the calcineurin-dependent pathway in C. albicans , while GZF3 is a GATA-type transcription factor of unknown function in C. albicans . Overexpression of each gene resulted in an increase of FLC tolerance, however, only the deletion of CRZ1 in clinical FLC-tolerant strains consistently decreased their FLC tolerance. Transcription profiling of clinical isolates with variable levels of FLC tolerance confirmed a calcineurin-dependent signature in these isolates when exposed to FLC.

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Section: Discussionsupporting

confidence: 92%

Identification and Characterization of Mediators of Fluconazole Tolerance in Candida albicans

Delarze¹,

Brandt²,

Trachsel³

et al. 2020

Front. Microbiol.

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“…Consistent with this, the PR mutants grew better and displayed a transcriptomic profile similar to WT cells. These results are also interesting in that genomic analysis revealed that the different classes of PR mutants showed distinct mechanisms for mutation of BCY1 or deletion of parts of the left arm of chromosome 2 (Extended Data Table 1), which underscore how the plasticity of the C. albicans genome enables it to adapt to different kinds of stress from mutations or antifungal drugs 35, 36, 59, 60 .…”

Section: Discussionmentioning

confidence: 84%

Integrative multi-omics profiling reveals cAMP-independent mechanisms regulating hyphal morphogenesis inCandida albicans

Min

Jannace

et al. 2021

Preprint

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Microbial pathogens grow in a wide range of different morphologies that provide distinct advantages for virulence. In the fungal pathogen Candida albicans, adenylyl cyclase (Cyr1) has been thought to be a master regulator of the switch to invasive hyphal morphogenesis and biofilm formation. However, faster growing cyr1Δ/Δ pseudorevertant (PR) mutants were identified that form hyphae in the absence of cAMP. Isolation of additional PR mutants revealed that their improved growth was due to loss of one copy of BCY1, the negative regulatory subunit of protein kinase A, from the left arm of chromosome 2. Furthermore, hyphal morphogenesis was improved in some of PR mutants by multigenic haploinsufficiency resulting from loss of large regions of the left arm of chromosome 2, including global transcriptional regulators. Interestingly, hyphal-associated genes were also induced in a manner that was independent of cAMP. This indicates that basal protein kinase A activity is an important prerequisite to induce hyphae, but activation of the cAMP pathway is not needed. Instead, phosphoproteomic analysis indicated that the Cdc28 cyclin-dependent kinase and the casein kinase Yck2 play key roles in promoting polarized growth. In addition, integrating transcriptomic and proteomic data reveals hyphal stimuli induce increased production of key transcription factors that contribute to polarized morphogenesis.

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“…Furthermore, it is more and more evident that aneuploidy can actually also be beneficial for adaptation, especially when gene expression issues are resolved [ 67 ]. Indeed, aneuploidies were shown to drive the adaptation to different types of environmental stress, including limiting nutrients, high ethanol concentration, heat shock, oxidative stress, endoplasmic reticulum stress, and drug resistance [ 31 , 92 , 93 , 155 , 194 , 195 , 196 , 197 , 198 , 199 , 200 , 201 ]. In addition, aneuploidy has been shown to help suppress certain genetic mutations such as telomerase insufficiency [ 202 , 203 ], cytokinesis perturbation [ 91 ], disruption of essential nucleoporin genes [ 204 ] and loss of a small ubiquitin-related modifier protease [ 205 ].…”

Section: Aneuploidy and Segmental Duplications: A “Quick Fix” For Evolutionary Adaptation?mentioning

confidence: 99%

The Role of Structural Variation in Adaptation and Evolution of Yeast and Other Fungi

Gorkovskiy

Verstrepen

2021

Genes

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Mutations in DNA can be limited to one or a few nucleotides, or encompass larger deletions, insertions, duplications, inversions and translocations that span long stretches of DNA or even full chromosomes. These so-called structural variations (SVs) can alter the gene copy number, modify open reading frames, change regulatory sequences or chromatin structure and thus result in major phenotypic changes. As some of the best-known examples of SV are linked to severe genetic disorders, this type of mutation has traditionally been regarded as negative and of little importance for adaptive evolution. However, the advent of genomic technologies uncovered the ubiquity of SVs even in healthy organisms. Moreover, experimental evolution studies suggest that SV is an important driver of evolution and adaptation to new environments. Here, we provide an overview of the causes and consequences of SV and their role in adaptation, with specific emphasis on fungi since these have proven to be excellent models to study SV.

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Expandable and reversible copy number amplification drives rapid adaptation to antifungal drugs

Cited by 108 publications

References 188 publications

Identification and Characterization of Mediators of Fluconazole Tolerance in Candida albicans

Identification and Characterization of Mediators of Fluconazole Tolerance in Candida albicans

Integrative multi-omics profiling reveals cAMP-independent mechanisms regulating hyphal morphogenesis inCandida albicans

The Role of Structural Variation in Adaptation and Evolution of Yeast and Other Fungi

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