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CORDIS

Control of Bacterial Multidrug Tolerance and Stress Response by Alarmone Synthetase SpoT

Project description

Insight into bacterial survival mechanisms

Bacteria adapt to new environmental conditions and survive nutritional deprivation or antibiotics by activating the stringent response, which is triggered by a small molecule known as (p)ppGpp. This regulatory system alters bacterial gene expression and metabolic activities to facilitate survival through the formation of a subpopulation of persister cells, usually dormant and highly tolerant to antibiotics. Funded by the European Research Council, the STRINGENCY project aims to investigate the mechanisms underlying the formation of perister cells and the modulation of the (p)ppGpp molecule. Results will provide fundamental understanding into bacterial survival with potential benefits for biotechnological processes but also open new perspectives for the treatment of bacterial infections.

Objective

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.

Host institution

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Net EU contribution
€ 1 494 042,00
Address
RUE MICHEL ANGE 3
75794 Paris
France

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Region
Ile-de-France Ile-de-France Paris
Activity type
Research Organisations
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Total cost
€ 1 494 042,00

Beneficiaries (1)