CRS-MIS in Candida glabrata: sphingolipids modulate echinocandin-Fks interaction.
CRS-MIS in Candida glabrata: sphingolipids modulate echinocandin-Fks interaction.
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DOI：
10.1111/j.1365-2958.2012.08194.x
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发表时间：
2012-10
影响因子：
3.6
通讯作者：
Edlind TD
中科院分区：
文献类型：
--
作者：
Healey KR;Katiyar SK;Raj S;Edlind TD
目前，抗唑性秃念珠菌感染常用棘白菌素caspofungin （CSF）或micafungin （MCF）治疗。对这些细胞壁合成脂肽抑制剂的真正抗性（>易感性降低32倍）是罕见的，并且与整体膜蛋白Fks1或Fks2的突变密切相关。相比之下，在体外很容易选择具有4至32倍CSF敏感性降低（CRS）的突变体，并且令人惊讶地显示具有4至32倍MCF敏感性增加（MIS）。测序和基因缺失表明，CRS-MIS是不依赖于fks的。为了探索其他机制，我们最初使用了酿酒酵母，并观察到CRS是由多个突变（fen1Δ， sur4Δ， cka2Δ和tsc10-ts）破坏鞘脂生物合成而产生的。根据这一线索，构建了C. glabrata fen1Δ和cka2Δ deleters，并显示出CRS-MIS。CRS-MIS实验室突变体和临床分离株的鞘脂分析显示，二氢鞘磷脂（DHS）和植物鞘磷脂（PHS）水平升高，并且与测序结果一致，发现了fen1、sur4、ifa38和sur2突变。此外，外源DHS或PHS使野生型光棘草具有CRS-MIS表型。然而，外源性小灵通未能抑制DHS向小灵通转化受阻的sur2突变体中的CRS-MIS，这意味着这些中间体的积累赋予了CRS-MIS。我们得出结论鞘脂膜调节棘白素- fks相互作用。
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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影响因子：
4.9
作者：
Katiyar, Santosh;Pfaller, Michael;Edlind, Thomas
通讯作者：
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