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

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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.