Descrizione del progetto
Approfondire i meccanismi di sopravvivenza dei batteri
I batteri si adattano a nuove condizioni ambientali e sopravvivono alla deprivazione di alimenti o agli antibiotici attivando la risposta stringente, che viene innescata da una piccola molecola nota come (p)ppGpp. Questo sistema di regolazione altera l’espressione genica e le attività metaboliche dei batteri per facilitare la sopravvivenza attraverso la formazione di una sottopopolazione di cellule «persistenti», solitamente dormienti e altamente tolleranti agli antibiotici. Finanziato dal Consiglio europeo della ricerca, il progetto STRINGENCY si propone di studiare i meccanismi alla base della formazione di questo tipo di cellule e della modulazione della molecola (p)ppGpp. I risultati forniranno una comprensione fondamentale della sopravvivenza batterica, offrendo potenziali vantaggi per i processi biotecnologici, e apriranno inoltre nuove prospettive per il trattamento delle infezioni batteriche.
Obiettivo
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.
Campo scientifico
- natural sciencesbiological sciencesmicrobiologybacteriology
- natural sciencesbiological sciencesbiochemistrybiomoleculeslipids
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsantibiotics
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes
- natural sciencesbiological sciencesmolecular biology
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-STG - Starting GrantIstituzione ospitante
75794 Paris
Francia