Cryptococcus neoformans Resistance to Echinocandins: (1,3)β-Glucan Synthase Activity Is Sensitive to Echinocandins

Maligie, Marybeth A.; Selitrennikoff, Claude P.

doi:10.1128/aac.49.7.2851-2856.2005

Cited by 178Fungal Infections and StudiesAntifungal resistance and susceptibilityFungal and yeast genetics research

Cryptococcus neoformans Resistance to Echinocandins: (1,3)β-Glucan Synthase Activity Is Sensitive to Echinocandins

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Maligie, Marybeth A., Selitrennikoff, Claude P.·2005·Antimicrobial Agents and Chemotherapy

DOI 10.1128/aac.49.7.2851-2856.2005PMC PMC1168702

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Abstract

(1,3)β- d -Glucan synthase (EC 2.4.1.34. UDP-glucose: 1,3-β- d -glucan 3-β-glucosyltransferase) uses UDP-glucose as substrate and catalyzes the polymerization of glucose ([1,3]-β-linkages) to form the major carbohydrate component of the fungal cell wall. We have optimized in vitro assay conditions for (1,3)β-glucan synthase activity from Cryptococcus neoformans . Cells lysed in 50 mM Tris, pH 7.75, containing 20% glycerol, 2 mM NaF, 1 mM dithiothreitol, 0.1 mM phenylmethylsulfonyl fluoride, 5 mM MgCl 2 , 0.1% protease and phosphatase inhibitor cocktails, and 60 μM GTPγS produced maximum specific activity in vitro. We tested in vitro C. neoformans (1,3)β-glucan synthase activity against the (1,3)β-glucan synthase inhibitors, caspofungin and cilofungin, and have determined that (1,3)β-glucan synthase activity is very sensitive (apparent K i of 0.17 ± 0.02 μM and 22 ± 5.7 μM, respectively) to these echinocandins. Taken together with high MICs for C. neoformans (caspofungin MIC, 16 μg/ml; cilofungin MIC, 64 μg/ml), our results indicate that C. neoformans is resistant to caspofungin and cilofungin by a mechanism(s) unrelated to (1,3)β-glucan synthase resistance.

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The resistance of Cryptococcus to echinocandins is paradoxical because β-1,3-glucan synthase, the enzymatic target of echinocandins, is essential in Cryptococcus and has been demonstrated to be potently inhibited by echinocandins biochemically.
“This resistance is paradoxical, as β-1,3-glucan synthase, the enzymatic target of the echinocandins, is essential in Cryptococcus and has been demonstrated to be potently inhibited by echinocandins biochemically44,45.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [45]

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Authors: Maligie, M. A., & Selitrennikoff, C. P.
Affiliations: University of Colorado Health (US)
ORCID: Selitrennikoff, Claude P.
Venue: Antimicrobial Agents and Chemotherapy
Publisher: American Society for Microbiology
Published: 2005-07
Volume: 49
Issue: 7
Pages: 2851-2856
ISSN: 0066-4804 (ISSN-L)
1098-6596
DOI: 10.1128/aac.49.7.2851-2856.2005
PMC: PMC1168702
OpenAlex: W2128575896
Cited by: 178
References: 52
Citations by year: 2026: 10 · 2025: 8 · 2024: 7 · 2023: 13 · 2022: 11 · 2021: 13 · 2020: 14 · 2019: 9 · 2018: 10 · 2017: 10 · 2016: 10 · 2015: 3 · 2014: 9 · 2013: 4 · 2012: 4
FWCI: 4.30
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Antimicrobial Agents and Chemotherapy (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health
National Institute of Allergy and Infectious Diseases (1 R21 AI05883)
Topics: Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
Keywords: Cryptococcus neoformans, echinocandin resistance, caspofungin, beta-1,3-glucan synthase, fungal cell wall, UDP-glucose, enzyme inhibition, minimum inhibitory concentration, antifungal resistance
MeSH terms: Caspofungin, Antifungal Agents, Cryptococcus neoformans, Fungal Proteins, Glucosyltransferases, Humans, Microbial Sensitivity Tests, Peptides, Cyclic, Drug Resistance, Fungal, Echinocandins, Lipopeptides

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Cryptococcus neoformans Resistance to Echinocandins: (1,3)β-Glucan Synthase Activity Is Sensitive to Echinocandins

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