Senescence of Staphylococci: The roles of Clp ATPases in bacterial metabolism, survival and persistence during late stationary phase

由金黄色葡萄球菌引起的疾病通常会持续一个慢性过程，而且这种感染很难治疗。金黄色葡萄球菌已经发展出各种胁迫反应系统，允许毒力因子的协调表达和对环境条件的适应。CLP-ATPase/蛋白水解酶复合体是高度保守的蛋白质再激活和降解系统，在应激反应中起主要作用。在不同的细菌物种中，CLP复合体的作用与细菌的能力、细胞壁合成、毒力和其他生理特性有关。最近，在金黄色葡萄球菌中，各种CLP ATPase被发现影响全球调节功能，导致复杂的表型变化。我们已经证明，ClpC通过功能上的TCA循环代谢，允许细菌在静止后重新生长并进入死亡阶段，我们得出结论，ClpC可能在长期生存中发挥重要的调节作用。在这里，我们建议扩展与其他金黄色葡萄球菌CLP ATPase相比，ClpC在金黄色葡萄球菌衰老、存活和程序性细胞死亡等晚期现象中的作用特征。用代谢组学方法对调节修饰进行全球分析将使金黄色葡萄球菌ClpC具有更详细的特征。因此，计划中的研究将有助于揭开CLP-ATPase在慢性持续性疾病过程中的假定作用。

Disease caused by Staphylococcus aureus frequently takes a chronic persistent course, and such infections are difficult-to-treat. S. aureus has developed various stress response systems allowing for coordinated expression of virulence factors and adaptation to environmental conditions. Clp ATPase/protease complexes for protein reactivation and degradation are highly conserved systems with a primary function in stress response. In various bacterial species, the role of Clp complexes has been associated with competence, cell wall synthesis, virulence and other physiologic properties. More recently, in S. aureus various Clp ATPases have been found to influence global regulator functions resulting in complex phenotypic changes. We have shown that ClpC allows for poststationary regrowth and entry into the bacterial death phase through a functional TCA cycle metabolism, and we have concluded that ClpC may play a major regulatory role for long-term survival. Here we propose to extend the characterization of the role of ClpC compared to other S. aureus Clp ATPases with respect to late phase phenomena such as S. aureus senescence, survival, and programmed cell death. Global analyses of regulatory modifications with a metabolomic approach will allow to characterize S. aureus ClpC in further detail. Planned studies will thus help to unravel the putative role of Clp ATPases in chronicpersistent course of disease.