Projektbeschreibung
Die Überlebensmechanismen von Bakterien erforschen
Bakterien passen sich an neue Umweltbedingungen an und können Nährstoffmangel sowie Antibiotika überleben, indem sie die Stringent Response aktivieren, die durch ein kleines Molekül namens (p)ppGpp ausgelöst wird. Durch dieses Regulierungssystem verändern sich die bakterielle Genexpression und die Stoffwechselaktivitäten. So entsteht eine Untergruppe aus Persister-Zellen, um das Überleben zu sichern. Diese Zellen sind meist inaktiv und weisen eine hohe Toleranz gegenüber Antibiotika auf. Im Zuge des vom Europäischen Forschungsrat finanzierten Projekts STRINGENCY sollen die Mechanismen erforscht werden, die der Bildung von Persister-Zellen und der Modulation des Moleküls (p)ppGpp zugrunde liegen. Die Ergebnisse werden zu einem grundlegenden Verständnis des bakteriellen Überlebens beitragen, mit einem möglichen Nutzen für biotechnologische Verfahren, aber auch neue Perspektiven für die Behandlung bakterieller Infektionen eröffnen.
Ziel
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.
Wissenschaftliches Gebiet
- natural sciencesbiological sciencesmicrobiologybacteriology
- natural sciencesbiological sciencesbiochemistrybiomoleculeslipids
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsantibiotics
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes
- natural sciencesbiological sciencesmolecular biology
Programm/Programme
Thema/Themen
Finanzierungsplan
ERC-STG - Starting GrantGastgebende Einrichtung
75794 Paris
Frankreich