Nutritional Control of Antibiotic Resistance via an Interface between the Phosphotransferase System and a Two-Component Signaling System
Nutritional Control of Antibiotic Resistance via an Interface between the Phosphotransferase System and a Two-Component Signaling System
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DOI：
10.1128/aac.01919-13
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发表时间：
2013-11
影响因子：
4.9
通讯作者：
H. Snyder;Stephanie L. Kellogg;Laura M Skarda;Jaime L. Little;C. Kristich
中科院分区：
文献类型：
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作者：
H. Snyder;Stephanie L. Kellogg;Laura M Skarda;Jaime L. Little;C. Kristich
摘要 肠球菌是胃肠道 (GI) 中普遍存在的居民。然而，耐抗生素肠球菌也是医院获得性感染的主要原因。肠球菌本质上对头孢菌素具有耐药性，在头孢菌素治疗期间，肠球菌能够在患者胃肠道中生长到异常高的密度，从而促进传播到引起感染的其他部位。尽管头孢菌素耐药性很重要，但关于头孢菌素耐药性的根本原因仍然存在许多问题。粪肠球菌对头孢菌素耐药需要一个特定的双组分信号系统，由 CroS 传感器激酶及其同源反应调节器 (CroR) 组成，但人们对控制该信号系统调节耐药性的因素知之甚少。为了探索 CroR 参与影响头孢菌素耐药性的信号网络，我们采用蛋白质片段互补测定来检测粪肠球菌细胞中的蛋白质-蛋白质相互作用，揭示了 CroR 与磷酸转移酶系统 (PTS) 的 HPr 蛋白之间以前未知的关联，该磷酸转移酶系统 (PTS) 负责碳水化合物的摄取和基因表达的分解代谢控制。遗传和生理分析表明，与 HPr 的关联限制了 CroR 以营养依赖性方式促进头孢菌素抗性和基因表达的能力。突变分析表明 HPr 用于与 CroR 关联的界面不同于用于与其他细胞伙伴关联的界面。我们的结果定义了粪肠球菌中关键的营养响应信号系统（PTS）和驱动抗生素耐药性的双组分信号系统之间的物理和功能联系，并且他们提出了细菌可以将其营养状况与不同环境刺激相结合的总体策略。
ABSTRACT Enterococci are ubiquitous inhabitants of the gastrointestinal (GI) tract. However, antibiotic-resistant enterococci are also major causes of hospital-acquired infections. Enterococci are intrinsically resistant to cephalosporins, enabling growth to abnormally high densities in the GI tract in patients during cephalosporin therapy, thereby promoting dissemination to other sites where they cause infection. Despite its importance, many questions about the underlying basis for cephalosporin resistance remain. A specific two-component signaling system, composed of the CroS sensor kinase and its cognate response regulator (CroR), is required for cephalosporin resistance in Enterococcus faecalis, but little is known about the factors that control this signaling system to modulate resistance. To explore the signaling network in which CroR participates to influence cephalosporin resistance, we employed a protein fragment complementation assay to detect protein-protein interactions in E. faecalis cells, revealing a previously unknown association of CroR with the HPr protein of the phosphotransferase system (PTS) responsible for carbohydrate uptake and catabolite control of gene expression. Genetic and physiological analyses indicate that association with HPr restricts the ability of CroR to promote cephalosporin resistance and gene expression in a nutrient-dependent manner. Mutational analysis suggests that the interface used by HPr to associate with CroR is distinct from the interface used to associate with other cellular partners. Our results define a physical and functional connection between a critical nutrient-responsive signaling system (the PTS) and a two-component signaling system that drives antibiotic resistance in E. faecalis, and they suggest a general strategy by which bacteria can integrate their nutritional status with diverse environmental stimuli.