Description du projet
Mieux comprendre les mécanismes de survie des bactéries
Les bactéries s’adaptent à de nouvelles conditions environnementales et survivent à la privation d’apport nutritif ou aux antibiotiques en activant la réponse stringente, qui est déclenchée par une petite molécule, la (p)ppGpp. Ce système de régulation modifie l’expression des gènes bactériens et les activités métaboliques afin de faciliter la survie par la formation d’une sous-population de cellules persisters, généralement dormantes et extr^emement tolérantes aux antibiotiques. Financé par le Conseil européen de la recherche, le projet STRINGENCY se propose d’étudier les mécanismes sous-jacents à la formation des cellules persisters et à la modulation de la molécule (p)ppGpp. Les résultats apporteront non seulement une compréhension fondamentale de la survie bactérienne, avec des avantages potentiels pour les processus biotechnologiques, mais ouvriront également de nouvelles perspectives pour le traitement des infections bactériennes.
Objectif
Difficult-to-treat chronic and recurrent bacterial infections are often caused by bacteria that are sensitive to commonly used antibiotics. The reasons for this recalcitrance are frequently unknown. However, when grown in the laboratory, all bacteria, including major pathogens form persister cells that are multidrug tolerant, a phenomenon thought to be a major factor underlying recalcitrant infections. We observed that the general bacterial stress response, known as “the stringent response”, plays a key role in persister cell maintenance. Indeed, stochastic variation of the stringent response regulator ppGpp triggers persister cell formation. However, the molecular mechanisms by which environmental cues activate the stringent response are still largely unknown and represent one of the most fundamental, unsolved problems in prokaryotic molecular biology. Importantly the stringent response is also required for virulence of almost all bacterial pathogens, strongly arguing that novel insights into ppGpp biology will lead to novel methods to combat infections. We recently observed that the ppGpp synthetase II activity encoded by SpoT is responsible for persister cell formation in Escherichia. coli. Therefore, I propose a research program that builds on the pivotal role of SpoT in bacterial persistence, with the goal of dissecting the molecular mechanisms by which environmental stimuli trigger SpoT-dependent ppGpp synthesis. This project has three main objectives: (i) To unravel how spoT expression is regulated (ii) To reveal how ppGpp synthetase II activity is mechanistically controlled and (iii) To decipher the physiological role of SpoT in persister cell decision-making. The program is ambitious and will provide a significant step forward for the persistence field and offer novel, fundamental insights into ppGpp biology. Moreover, it may represent an invaluable resource to improve biotechnological processes and how bacterial infections are treated.
Champ scientifique
- natural sciencesbiological sciencesmicrobiologybacteriology
- natural sciencesbiological sciencesbiochemistrybiomoleculeslipids
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsantibiotics
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes
- natural sciencesbiological sciencesmolecular biology
Programme(s)
Thème(s)
Régime de financement
ERC-STG - Starting GrantInstitution d’accueil
75794 Paris
France