Reciprocal Regulation of Cephalosporin Resistance in Enterococcus faecalis
Reciprocal Regulation of Cephalosporin Resistance in Enterococcus faecalis
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DOI：
10.1128/mbio.00199-11
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发表时间：
2011-11-01
期刊：
影响因子：
6.4
通讯作者：
Hoff, Jessica S.
中科院分区：
文献类型：
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作者：
Kristich, Christopher J.;Little, Jaime L.;Hoff, Jessica S.
耐抗生素肠球菌是医院获得性感染的主要原因，因此是一个严重的公共卫生问题。获得医院获得性肠球菌感染的一个众所周知的危险因素是既往接受过广谱头孢菌素抗生素治疗。由于肠球菌属的固有头孢菌素耐药性，肠球菌可以在接受头孢菌素治疗的患者中增殖。然而，粪肠球菌对头孢菌素耐药的分子基础尚未得到充分阐明。之前我们确定了粪肠球菌内在头孢菌素耐药性需要一种推定的 Ser/Thr 激酶 IreK（以前称为 PrkC）。在这里，我们表明激酶活性是头孢菌素耐药性所必需的，此外，粪肠球菌中的耐药性受到 IreK 和 IreP 的相互调节，IreP 是 IreK 紧邻上游编码的 PP2C 型蛋白磷酸酶。缺乏 IreP 的两种不同谱系的粪肠球菌突变体对头孢菌素表现出显着的高耐药性，但对针对其他细胞过程的抗生素没有显着的高耐药性。进一步的遗传分析表明 IreP 突变体的高抗性是由 IreK 激酶介导的。此外，竞争实验表明，超耐药 Delta ireP 突变体在没有抗生素的情况下表现出明显的适应性缺陷，为使用复杂的信号系统来控制内在的头孢菌素耐药性提供了进化原理。这些结果支持了一种模型，其中 IreK 和 IreP 作为信号转导回路的一部分，通过蛋白质磷酸化和去磷酸化发挥拮抗作用，调节细胞对头孢菌素诱导的应激的适应。 重要性 作为医院获得性感染的主要原因，抗生素耐药性肠球菌代表了一个严重的公共卫生问题。众所周知，肠球菌对广谱头孢菌素抗生素表现出内在耐药性，这一特性使其能够在接受头孢菌素治疗的患者体内增殖，从而使这些患者易于获得肠球菌感染。因此，抑制肠球菌头孢菌素耐药性可能是预防医院获得性肠球菌感染出现的有效新策略。然而，目前对粪肠球菌头孢菌素耐药性的分子基础知之甚少。我们的结果开始揭示一种新的磷酸化依赖性信号转导系统的细节，该系统控制肠球菌中的头孢菌素耐药性。更深入地了解粪肠球菌头孢菌素耐药机制可能有助于开发旨在降低医院获得性肠球菌感染发生率的新疗法。
Antibiotic-resistant enterococci are major causes of hospital-acquired infections and therefore represent a serious public health problem. One well-known risk factor for the acquisition of hospital-acquired enterococcal infections is prior therapy with broad-spectrum cephalosporin antibiotics. Enterococci can proliferate in patients undergoing cephalosporin therapy due to intrinsic cephalosporin resistance, a characteristic of the genus Enterococcus. However, the molecular basis for cephalosporin resistance in E. faecalis has yet to be adequately elucidated. Previously we determined that a putative Ser/Thr kinase, IreK (formerly PrkC), is required for intrinsic cephalosporin resistance in E. faecalis. Here we show that kinase activity is required for cephalosporin resistance and, further, that resistance in E. faecalis is reciprocally regulated by IreK and IreP, a PP2C-type protein phosphatase encoded immediately upstream of IreK. Mutants of two divergent lineages of E. faecalis lacking IreP exhibit remarkable hyperresistance to cephalosporins but not to antibiotics targeting other cellular processes. Further genetic analyses indicate that hyperresistance of the IreP mutant is mediated by the IreK kinase. Additionally, competition experiments reveal that hyperresistant Delta ireP mutants exhibit a substantial fitness defect in the absence of antibiotics, providing an evolutionary rationale for the use of a complex signaling system to control intrinsic cephalosporin resistance. These results support a model in which IreK and IreP act antagonistically via protein phosphorylation and dephosphorylation as part of a signal transduction circuit to regulate cellular adaptation to cephalosporin-induced stress.IMPORTANCE As a major cause of hospital-acquired infections, antibiotic-resistant enterococci represent a serious public health problem. Enterococci are well-known to exhibit intrinsic resistance to broad-spectrum cephalosporin antibiotics, a trait that enables them to proliferate in patients undergoing cephalosporin therapy, thereby predisposing these patients to acquisition of an enterococcal infection. Thus, inhibition of enterococcal cephalosporin resistance could represent an effective new strategy to prevent the emergence of hospital-acquired enterococcal infections. At this time, however, the molecular basis for cephalosporin resistance in E. faecalis is poorly understood. Our results begin to unravel the details of a new phosphorylation-dependent signal transduction system that controls cephalosporin resistance in enterococci. Deeper understanding of the mechanism underlying cephalosporin resistance in E. faecalis may enable the development of new therapeutics designed to reduce the incidence of hospital-acquired enterococcal infections.