Journal article
CRS–MIS in Candida glabrata: sphingolipids modulate echinocandin–Fks interaction
Molecular microbiology, v 86(2), pp 303-313
Oct 2012
PMID: 22909030
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Summary
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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Details
- Title
- CRS–MIS in Candida glabrata: sphingolipids modulate echinocandin–Fks interaction
- Creators
- Kelley R Healey - Drexel University College of MedicineSantosh K Katiyar - Drexel University College of MedicineShriya Raj - Drexel University College of MedicineThomas D Edlind - Drexel University College of Medicine
- Publication Details
- Molecular microbiology, v 86(2), pp 303-313
- Publisher
- Wiley
- Number of pages
- 11
- Grant note
- National Institutes of Health (AI075272)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000309756500006
- Scopus ID
- 2-s2.0-84867469852
- Other Identifier
- 991014878103004721
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InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Web of Science research areas
- Biochemistry & Molecular Biology
- Microbiology