Project Details
Projekt
Mechanisms of (p)ppGpp action in Staphylococcus aureus
Applicant
Professorin Dr. Christiane Wolz
Subject Area
Metabolism, Biochemistry and Genetics of Microorganisms
Term
from 2019 to 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 423246275
The stringent response of bacteria is characterised by the synthesis of the messenger molecule (p)ppGpp, which interferes with many cellular processes, including transcription, replication and translation. However, the phenotypic consequences resulting from (p)ppGpp accumulation vary among species and can be mediated by different underlying mechanisms. Depending on the species, the stringent response is crucial for diverse biological processes, including differentiation, biofilm formation, antibiotic tolerance, production of secondary metabolites or virulence. It is now clear that there are fundamental differences between the stringent response initially characterised in E. coli and the response in Firmicutes. Differences are seen in both the main players involved in synthesis and degradation of the messengers and in the downstream effects of (p)ppGpp. We elucidated major players and mechanisms of the stringent response in Staphylococcus aureus. In S. aureus the stringent response plays important roles in virulence, phagosomal escape and antibiotic tolerance. From our previous work we identified several genes that are immediately activated upon (p)ppGpp synthesis. The molecular mechanisms of gene activation during the stringent response are not well understood, but such gene activation is important for survival under stress conditions probably in a species specific manner. We aim to unravel the molecular mechanisms and functional consequences of (p)ppGpp-dependent gene activation. Furthermore, we will develop (p)ppGpp sensors to assess the role of possibly stochastic (p)ppGpp synthesis in stress tolerance on the single cell level. Recently, major structural insights concerning the (p)ppGpp synthetase activities of Rel, RelQ and RelP from Firmicutes were gained. However, many of the proposed mechanisms are not yet confirmed in vivo in living organisms. We will establish methods to gain insights into the functional consequence of the allosteric regulation of the (p)ppGpp synthetase/hydrolase activities in S. aureus. With this project we will elucidate the underlying molecular mechanisms leading to the specific stringent response phenotype of S. aureus.
DFG Programme
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