ArticleMolecular microbiology2012
CRS-MIS in Candida glabrata: sphingolipids modulate echinocandin-Fks interaction.
Article in Molecular microbiology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed, 79 citations in OpenAlex.
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- Evolutionary dynamics in gut-colonizing Candida glabrata during caspofungin therapy: Emergence of clinically important mutations in sphingolipid biosynthesis.PLoS pathogens · 2024Article
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- Whole genome analysis of echinocandin non-susceptible Candida Glabrata clinical isolates: a multi-center study in China.BMC microbiology · 2023Article
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- Serine/Threonine Phosphatase Calcineurin Orchestrates the Intrinsic Resistance to Micafungin in the Human-Pathogenic Fungus Mucor circinelloides.Antimicrobial agents and chemotherapy · 2023Article
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- What 'Omics can tell us about antifungal adaptation.FEMS yeast research · 2022Review
- Echinocandin Drugs Induce Differential Effects in Cytokinesis Progression and Cell Integrity.Pharmaceuticals (Basel, Switzerland) · 2021Article
- Oceanapiside, a Marine Natural Product, Targets the Sphingolipid Pathway of Fluconazole-ResistantMarine drugs · 2021Article
- Sphingolipidomics of drug resistant Candida auris clinical isolates reveal distinct sphingolipid species signatures.Biochimica et biophysica acta. Molecular and cell biology of lipids · 2021Article
- Critical Assessment of Cell Wall Integrity Factors Contributing toFrontiers in microbiology · 2021Article
- Functions of Sphingolipids in Pathogenesis During Host-Pathogen Interactions.Frontiers in microbiology · 2021Review
- Rezafungin-Mechanisms of Action, Susceptibility and Resistance: Similarities and Differences with the Other Echinocandins.Journal of fungi (Basel, Switzerland) · 2020Review
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Infections with the azole-refractory yeast Candida glabrata are now commonly treated with the echinocandins caspofungin (CSF) or micafungin (MCF). True resistance (> 32-fold decreased susceptibility) to these lipopeptide inhibitors of cell wall synthesis is rare and strictly associated with mutations in integral membrane proteins Fks1 or Fks2. In contrast, mutants exhibiting 4- to 32-fold CSF reduced susceptibility (CRS) were readily selected in vitro, and surprisingly demonstrated 4- to 32-fold MCF increased susceptibility (MIS). Sequencing and gene deletion demonstrated that CRS-MIS is Fks-independent. To explore alternative mechanisms, we initially employed Saccharomyces cerevisiae, and observed that CRS was conferred by multiple mutations (fen1Δ, sur4Δ, cka2Δ and tsc10-ts) disrupting sphingolipid biosynthesis. Following this lead, C. glabrata fen1Δ and cka2Δ deletants were constructed, and shown to exhibit CRS-MIS. Sphingolipid analysis of CRS-MIS laboratory mutants and clinical isolates demonstrated elevated dihydrosphingosine (DHS) and phytosphingosine (PHS) levels, and consistent with this sequencing revealed fen1, sur4, ifa38 and sur2 mutations. Moreover, exogenous DHS or PHS conferred a CRS-MIS phenotype on wild-type C. glabrata. Exogenous PHS failed, however, to suppress CRS-MIS in a sur2 mutant blocked in conversion of DHS to PHS, implying that accumulation of these intermediates confers CRS-MIS. We conclude that membrane sphingolipids modulate echinocandin-Fks interaction.
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