Roles for Stress Response and Cell Wall Biosynthesis Pathways in Caspofungin Tolerance in Cryptococcus neoformans

Pianalto, Kaila M; Billmyre, R Blake; Telzrow, Calla L; Alspaugh, J Andrew

doi:10.1534/genetics.119.302290

Cited by 41Fungal and yeast genetics researchAntifungal resistance and susceptibilityFungal Infections and Studies

Roles for Stress Response and Cell Wall Biosynthesis Pathways in Caspofungin Tolerance in Cryptococcus neoformans

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Pianalto, Kaila M, Billmyre, R Blake, Telzrow, Calla L, Alspaugh, J Andrew·2019·Genetics

DOI 10.1534/genetics.119.302290PMC PMC6727808

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Abstract

Limited antifungal diversity and availability are growing problems for the treatment of fungal infections in the face of increasing drug resistance. The echinocandins, one of the newest classes of antifungal drugs, inhibit production of a crucial cell wall component. However, these compounds do not effectively inhibit the growth of the opportunistic fungal pathogen Cryptococcus neoformans, despite potent inhibition of the target enzyme in vitro. Therefore, we performed a forward genetic screen to identify cellular processes that mediate the relative tolerance of this organism to the echinocandin drug caspofungin. Through these studies, we identified 14 genetic mutants that enhance caspofungin antifungal activity. Rather than directly affecting caspofungin antifungal activity, these mutations seem to prevent the activation of various stress-induced compensatory cellular processes. For example, the pfa4Δ mutant has defects in the palmitoylation and localization of many of its target proteins, including the Ras1 GTPase and the Chs3 chitin synthase, which are both required for caspofungin tolerance. Similarly, we have confirmed the link between caspofungin treatment and calcineurin signaling in this organism, but we suggest a deeper mechanism in which caspofungin tolerance is mediated by multiple pathways downstream of calcineurin function. In summary, we describe here several pathways in C. neoformans that contribute to the complex caspofungin tolerance phenotype in this organism.

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These data highlight a pivotal role of stress responses in mediating echinocandin resistance, exemplified by the identification of 14 caspofungin-sensitive C. neoformans mutants that are defective in the activation of stress responses, including calcineurin-dependent responses.
“These data highlight a pivotal role of stress responses in mediating echinocandin resistance, which is exemplified by the identification of 14 caspofungin-sensitive C. neoformans mutants that are defective in the activation of stress responses, including calcineurin-dependent responses48.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [48]

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Authors: Pianalto, K. M., Billmyre, R. B., Telzrow, C. L., & Alspaugh, J. A.
Affiliations: Duke University (US)
Corresponding author: Alspaugh, J Andrew
ORCID: Pianalto, Kaila M
Billmyre, R Blake
Telzrow, Calla L
Alspaugh, J Andrew
Venue: Genetics
Publisher: Oxford University Press (OUP)
Published: 2019-09-01
Volume: 213
Issue: 1
Pages: 213-227
ISSN: 0016-6731 (ISSN-L)
1943-2631
DOI: 10.1534/genetics.119.302290
PMC: PMC6727808
OpenAlex: W2953441814
Cited by: 41
References: 106
Citations by year: 2026: 3 · 2025: 7 · 2024: 7 · 2023: 4 · 2022: 3 · 2021: 7 · 2020: 8 · 2019: 2
FWCI: 1.66
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
Locations: Genetics (publishedVersion)
bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: U.S. Department of Defense (32 CFR 168 a)
National Institutes of Health (NIH-R01, R01‐grant, AI074677)
National Institute of Allergy and Infectious Diseases (P01AI104533, R01AI074677, R01AI100272)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
Keywords: Cryptococcus neoformans, caspofungin, antifungal resistance, stress response, cell wall biosynthesis, calcineurin signaling, forward genetic screen, opportunistic fungal pathogens
MeSH terms: Caspofungin, Antifungal Agents, Cell Wall, Chitin Synthase, Cryptococcus neoformans, Fungal Proteins, Genes, Fungal, Stress, Physiological, ras Proteins, Calcineurin, Drug Resistance, Fungal

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Roles for Stress Response and Cell Wall Biosynthesis Pathways in Caspofungin Tolerance in Cryptococcus neoformans

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