Molecular Basis of Cell Membrane Adaptation in Daptomycin-Resistant Enterococcus faecalis.
Molecular Basis of Cell Membrane Adaptation in Daptomycin-Resistant Enterococcus faecalis.
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达托霉素耐药粪肠球菌细胞膜适应的分子基础。
DOI：
10.1101/2023.08.02.551704
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Arias,CesarA
中科院分区：
文献类型：
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作者：
Nguyen,AprilH;Tran,TrucT;Panesso,Diana;Hood,Kara;Polamraju,Vinathi;Zhang,Rutan;Khan,Ayesha;Miller,WilliamR;Mileykovskaya,Eugenia;Shamoo,Yousif;Xu,Libin;Vitrac,Heidi;Arias,CesarA
达托霉素是破坏细胞膜（CM）和肽聚糖稳态的最后手段脂肽抗生素。粪肠球菌已经开发出一种复杂的机制，通过将CM阴离子磷脂从隔膜中重新分布来避免达托霉素的杀伤。CM的变化是由一个3-组分的调节系统，指定LiaFSR，心磷脂合酶（Cls）的可能的贡献。然而，LiaFSR控制CM反应的机制和Cls的作用尚不清楚。在这里，我们表明，心磷脂合酶的活性是必不可少的阴离子磷脂再分配和达托霉素耐药，因为删除2个基因（cls 1和cls 2）编码Cls废除CM重塑。我们确定了LiaY，由LiaFSR调节的跨膜蛋白，和Cls 1作为阴离子磷脂微结构域重新分布所需的CM重塑的重要介质。我们的见解共同提供了肠球菌对细胞被膜抗生素反应的机制框架，可以在治疗上加以利用。
Daptomycin is a last-resort lipopeptide antibiotic that disrupts cell membrane (CM) and peptidoglycan homeostasis. Enterococcus faecalis has developed a sophisticated mechanism to avoid daptomycin killing by redistributing CM anionic phospholipids away from the septum. The CM changes are orchestrated by a 3-component regulatory system, designated LiaFSR, with a possible contribution of cardiolipin synthase (Cls). However, the mechanism by which LiaFSR controls the CM response and the role of Cls are unknown. Here, we show that cardiolipin synthase activity is essential for anionic phospholipid redistribution and daptomycin resistance since deletion of the 2 genes (cls1 and cls2) encoding Cls abolished CM remodeling. We identified LiaY, a transmembrane protein regulated by LiaFSR, and Cls1 as important mediators of CM remodeling required for redistribution of anionic phospholipid microdomains. Together, our insights provide a mechanistic framework on the enterococcal response to cell envelope antibiotics that could be exploited therapeutically.