Descripción del proyecto
La persistencia no siempre es un rasgo deseable
La persistencia ante la adversidad suele verse recompensada con la victoria ante los obstáculos, aunque por desgracia para nosotros, esto no es así para muchas bacterias sometidas al ataque de los antibióticos. Si bien se ha prestado mucha atención a la resistencia antimicrobiana, la llamada persistencia es un problema de salud pública igualmente complicado. Los persistentes bacterianos que pueden despertar cuando termina un tratamiento antibiótico poseen una vía importante que media la «respuesta astringente» que no presentan los mamíferos. A pesar de las importantes investigaciones realizadas sobre esta vía ubicua en las bacterias, hasta ahora, un mayor conocimiento no se ha traducido en métodos bioquímicos para modularla y combatir la ineficacia de algunos antibióticos. El proyecto financiado con fondos europeos PP-MAGIC investiga los mecanismos moleculares de la respuesta astringente con el objetivo de inhibirla con luz. La información podría conducir a nuevos tratamientos contra este subgrupo de bacterias, de forma que se minimizaría la incidencia de las infecciones bacterianas crónicas.
Objetivo
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.
Ámbito científico
- natural sciencesbiological sciencesmicrobiologybacteriology
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsantibiotics
- natural sciencesbiological sciencesgeneticsnucleotides
- natural sciencesbiological scienceszoologymammalogy
Programa(s)
Régimen de financiación
ERC-COG - Consolidator GrantInstitución de acogida
79098 Freiburg
Alemania