Description du projet
La persistance n’est pas toujours un attribut souhaitable
La persistance face à l’adversité est souvent récompensée par une victoire sur les obstacles; malheureusement pour nous, cela s’applique également aux nombreuses bactéries attaquées par les antibiotiques. Alors qu’une grande attention a été accordée à la résistance antimicrobienne, la persistance est un problème en matière de santé publique tout aussi complexe. Les cellules bactériennes persistantes qui peuvent revivre après l’arrêt du traitement antibiotique comportent une importante voie induisant la «réponse stricte» qui n’est pas observée chez les mammifères. Malgré d’importantes recherches sur cette voie omniprésente chez les bactéries, les connaissances accrues n’ont pas encore été traduites en approches biochimiques pour la moduler et combattre l’inefficacité de certains antibiotiques. Le projet PP-MAGIC, financé par l’UE, étudie les mécanismes moléculaires de cette réponse stricte en vue de l’inhiber à l’aide de la lumière. Ces informations pourraient déboucher sur de nouveaux traitements contre ce sous-groupe de bactéries, minimisant ainsi l’apparition d’infections bactériennes chroniques.
Objectif
The abusive use of antibiotics has led to multidrug-resistant bacteria and the acute threat of a post-antibiotic era. However, apart from resisters, there is a subgroup of bacteria called persisters that surviveby recalcitrance to antibiotic treatment. Persisters are not resistant to antibiotics but simply survive by metabolic shutdown. Upon withdrawal of antibiotics, these persisters resuscitate and regenerate the colony. They are heavily involved in failure of antibiotic treatment and the development of chronic infections. Bacterial persistence is controlled by the stringent response, which itself is mediated by hyperphosphorylated nucleotides, known as the magic spot (MS) nucleotides or (p)ppGpp. The importance of the stringent response, its omnipresence in the domain of bacteria, its connection to persister formation and tolerance to (antibiotic) stress, and its absence in mammals has led to significant research in microbiology. However, until recently these activities have not been paralleled by the development of chemical biology approaches. The current proposal aims to fill this gap by research into
(1) synthetic methodology targeting the magic spot nucleotides and their analogs,
(2) tools to identify target proteins of (p)ppGpp, and more generally (p)ppNpp
(3) analytical approaches to extract, resolve, and quantify (p)ppGpp,
(4) strategies to control the stringent response and persister formation with light
(5) inhibitors of the stringent response.
These new tools will enable a detailed understanding of the stringent response and thus ultimately help in the design of new antibiotics effective against persisters. The goal is to develop methods to force bacteria into the persistent state or inversely wake them up by using light and small molecules. Forcing bacteria out of persistence and blocking their entry into this state in combination with antibiotic treatment is a highly promising strategy to avoid the development of chronic bacterial infections.
Champ scientifique
- natural sciencesbiological sciencesmicrobiologybacteriology
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsantibiotics
- natural sciencesbiological sciencesgeneticsnucleotides
- natural sciencesbiological scienceszoologymammalogy
Programme(s)
Régime de financement
ERC-COG - Consolidator GrantInstitution d’accueil
79098 Freiburg
Allemagne