Daptomycin-resistant Enterococcus faecalis diverts the antibiotic molecule from the division septum and remodels cell membrane phospholipids.
Daptomycin-resistant Enterococcus faecalis diverts the antibiotic molecule from the division septum and remodels cell membrane phospholipids.
复制标题
达托霉素耐药粪肠球菌将抗生素分子从分裂隔膜转移并重塑细胞膜磷脂。
DOI：
10.1128/mbio.00281-13
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发表时间：
2013
期刊：
影响因子：
6.4
通讯作者：
Arias,CesarA
中科院分区：
文献类型：
--
作者：
Tran,TrucT;Panesso,Diana;Mishra,NagendraN;Mileykovskaya,Eugenia;Guan,Ziqianq;Munita,JoseM;Reyes,Jinnethe;Diaz,Lorena;Weinstock,GeorgeM;Murray,BarbaraE;Shamoo,Yousif;Dowhan,William;Bayer,ArnoldS;Arias,CesarA
由于缺乏可靠的治疗方案，耐多药肠球菌的治疗已成为世界各地医院的一个具有挑战性的临床问题。达托霉素（DAP）是一种细胞膜靶向阳离子抗菌脂肽，是目前唯一对万古霉素耐药肠球菌（VRE）具有体外杀菌活性的抗生素。然而，DAP对VRE的临床使用受到治疗期间出现耐药性的威胁，但导致DAP耐药性的机制尚未完全了解。DAP的作用机制涉及以钙依赖性方式与细胞膜相互作用，主要是在细菌隔膜水平。之前，我们证明了万古霉素耐药粪肠球菌中DAP耐药性的发展与编码具有两种主要功能的蛋白质的基因突变相关，（i）控制细胞包膜对抗生素和抗菌肽的应激反应（LiaFSR系统）和（ii）细胞膜磷脂代谢（甘油磷酸二酯磷酸二酯酶和心磷脂合酶）。在这项工作中，我们表明，这些VRE可以通过将抗生素从其主要靶点（分裂隔膜）转移到其他不同的细胞膜区域来抵抗DAP引起的细胞膜损伤。用耐DAP的E. faecalis是由细胞膜富含心磷脂的微结构域的初始再分布介导的，该微结构域与跨膜蛋白LiaF（参与细胞包膜稳态的三组分调节系统[LiaFSR]的成员）内的单个氨基酸缺失相关。DAP抗性的完全表达需要改变细胞膜磷脂含量的酶（甘油磷酸二酯磷酸二酯酶和心磷脂合酶）的额外突变。我们的研究结果描述了细菌对阳离子抗菌肽耐药的一种新机制。了解耐药机制对于开发对抗多重耐药微生物的新策略至关重要。万古霉素耐药肠球菌（VRE）是最常见的医院相关病原体之一，迫切需要新的治疗方法。达托霉素（DAP）是一种钙修饰的抗菌脂肽，其靶点是细菌细胞膜。目前的范例表明，革兰氏阳性细菌通过抗生素分子从带更多正电荷的细胞表面的静电排斥而变得对阳离子抗微生物肽具有抗性。在这项工作中，我们提供的证据表明，VRE使用一种新的策略，以避免DAP引起的杀戮。VRE不是将抗生素从细胞表面“排斥”，而是将抗生素分子从隔膜转移并将其“捕获”在不同的膜区域。我们提供了负责耐药机制的遗传和生化基础，并揭示了潜在抗菌剂开发的新靶点。
Treatment of multidrug-resistant enterococci has become a challenging clinical problem in hospitals around the world due to the lack of reliable therapeutic options. Daptomycin (DAP), a cell membrane-targeting cationic antimicrobial lipopeptide, is the only antibiotic within vitrobactericidal activity against vancomycin-resistant enterococci (VRE). However, the clinical use of DAP against VRE is threatened by emergence of resistance during therapy, but the mechanisms leading to DAP resistance are not fully understood. The mechanism of action of DAP involves interactions with the cell membrane in a calcium-dependent manner, mainly at the level of the bacterial septum. Previously, we demonstrated that development of DAP resistance in vancomycin-resistant Enterococcus faecalis is associated with mutations in genes encoding proteins with two main functions, (i) control of the cell envelope stress response to antibiotics and antimicrobial peptides (LiaFSR system) and (ii) cell membrane phospholipid metabolism (glycerophosphoryl diester phosphodiesterase and cardiolipin synthase). In this work, we show that these VRE can resist DAP-elicited cell membrane damage by diverting the antibiotic away from its principal target (division septum) to other distinct cell membrane regions. DAP septal diversion by DAP-resistant E. faecalis is mediated by initial redistribution of cell membrane cardiolipin-rich microdomains associated with a single amino acid deletion within the transmembrane protein LiaF (a member of a three-component regulatory system [LiaFSR] involved in cell envelope homeostasis). Full expression of DAP resistance requires additional mutations in enzymes (glycerophosphoryl diester phosphodiesterase and cardiolipin synthase) that alter cell membrane phospholipid content. Our findings describe a novel mechanism of bacterial resistance to cationic antimicrobial peptides.IMPORTANCEThe emergence of antibiotic resistance in bacterial pathogens is a threat to public health. Understanding the mechanisms of resistance is of crucial importance to develop new strategies to combat multidrug-resistant microorganisms. Vancomycin-resistant enterococci (VRE) are one of the most recalcitrant hospital-associated pathogens against which new therapies are urgently needed. Daptomycin (DAP) is a calcium-decorated antimicrobial lipopeptide whose target is the bacterial cell membrane. A current paradigm suggests that Gram-positive bacteria become resistant to cationic antimicrobial peptides via an electrostatic repulsion of the antibiotic molecule from a more positively charged cell surface. In this work, we provide evidence that VRE use a novel strategy to avoid DAP-elicited killing. Instead of “repelling” the antibiotic from the cell surface, VRE diverts the antibiotic molecule from the septum and “traps” it in distinct membrane regions. We provide genetic and biochemical bases responsible for the mechanism of resistance and disclose new targets for potential antimicrobial development.