CE44 - Biochimie du Vivant

Ionome and metabolic remodeling in the persistence and wake up of quiescent Salmonella – PERIOMET

Submission summary

The entry into a non-actively growing/quiescent state is a common strategy used by bacteria to survive under stressful conditions, including antibiotic treatment. Understanding quiescence is thus an important fundamental question, with relevance in the medical and environmental fields. However, our knowledge of mechanisms governing bacterial survival during this temporary arrest of proliferation or favoring exit from quiescence is limited. Extensive remodeling of gene expression is induced in these bacteria to reshape their membrane and metabolism and ensure their persistence. By using integrated global and analytical approaches, PERIOMET will investigate two important, but poorly understood (metabolism) or unexplored (ion homeostasis) aspects of this remodeling in the human pathogen Salmonella. Foodborne diseases caused by Salmonella represent a severe problem to the public health as well as the food industry. The objective is to reveal key features and rationally identify targets to devise novel strategies limiting the persistence of Salmonella and other pathogens in the environment, and their resistance to antibiotics.
The first part of the work is dedicated to the characterization, at the molecular and physiological levels, of a mechanism of control of the bacterial ionome that we have recently unraveled. We will determine how and why the intracellular concentration of metal ions, such as manganese, magnesium and cobalt, is strictly controlled during the entry of bacteria into quiescence. These ions are co-factors of many proteins and are essential for biological functions, such as metabolic activities and membrane stability, in actively dividing bacteria. They can also be toxic when they accumulate in excess. Very little is known about ions requirements and toxicity in non-actively growing bacteria. We will tackle this issue by deciphering the molecular mechanisms of the ionome control in quiescent cells and their impact on the physiology, resistance, lifespan and ability of quiescent cells to re-enter the proliferative cell cycle. In a second part of the project, we will explore the metabolic remodeling that takes place in quiescent bacteria and allows them to adapt and persist in adverse conditions. One important aspect that will be addressed is the phenotypic differentiation of quiescent populations into sub-populations of persister cells that survive in the presence of lethal concentrations of antibiotics and can lead to failure of antibiotic treatment. Understanding mechanisms governing bacterial persisters is an important topic. However, despites many studies, the physiological and molecular mechanisms controlling the formation of persisters are poorly understood. To address this complex issue and rationally identify targets to counteract persister formation, we will explore the recently discovered and unexpected compensatory effects of two mutations in the ability of quiescent cells to differentiate into persisters, and their modulation by cobalt. These studies will reveal the flexibility and extent of adaptive capacities of bacterial metabolism, but also weaknesses that could be exploited to propose potential targets and new antibacterial strategies. The originality and success of this work is based on the will of two teams with different expertise (metabolism, expression and regulation of the bacterial genome) to share their skills to achieve a common goal: understanding how bacterial populations use the entry into quiescence to reshape their metabolism and physiology and escape antibacterial strategies. By integrating modern and advanced technologies for global analyses of genome expression and metabolism and targeted analytical studies, this work will greatly extend our knowledge of survival mechanisms of quiescent bacteria and will identify key physiological and metabolic features favoring their persistence, against which novel antibacterial strategies can be designed.

Project coordination

Françoise NOREL (INSTITUT PASTEUR)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

LISBP LABORATOIRE D'INGÉNIERIE DES SYSTÈMES BIOLOGIQUES ET DES PROCÉDÉS
IP INSTITUT PASTEUR

Help of the ANR 378,639 euros
Beginning and duration of the scientific project: September 2019 - 48 Months

Useful links

Explorez notre base de projets financés

 

 

ANR makes available its datasets on funded projects, click here to find more.

Sign up for the latest news:
Subscribe to our newsletter