Projektbeschreibung
Antimikrobielle Resistenz: Entwicklung und Umgang
Der Missbrauch von Antibiotika hat zur Entwicklung der antimikrobiellen Resistenz bei Bakterien geführt. Die damit zusammenhängenden Gene werden in Bakterien horizontal über mobile genetische Elemente wie Plasmide übertragen und erlauben es den Bakterien, Antibiotika zu überleben. Jüngste Forschungen haben jedoch ergeben, dass entsprechende Plasmide auch Veränderungen in der Physiologie der bakteriellen Wirtszelle und der Empfindlichkeit gegenüber Antibiotika bewirken. Das vom Europäischen Forschungsrat finanzierte Projekt PLAS-FIGHTER zielt darauf ab, neue Strategien gegen Plasmid-vermittelte antimikrobielle Resistenz zu erarbeiten, indem spezifische Targets in Plasmid-tragenden Zellen ermittelt und Inhibitoren dieser Targets in einem breiten Spektrum von Bakterienstämmen unter unterschiedlichen ökologischen Bedingungen getestet werden. Dieser multidisziplinäre Ansatz wird zur Entwicklung neuer Strategien gegen antimikrobielle Resistenz beitragen.
Ziel
The discovery of antibiotics revolutionised the fight against infectious diseases and paved the way for modern medicine. However, widespread use of antibiotics has driven rampant evolution of antimicrobial resistance (AMR) in bacteria. The main route for AMR acquisition in clinically important bacteria is the horizontal transfer of plasmids (conjugation-competent mobile genetic elements) carrying resistance genes. AMR plasmids allow bacteria to survive antibiotics, but they also entail physiological alterations in the host cell. Recent results from my group and others reveal that AMR plasmids (i) produce a shared set of physiological alterations in the bacterial host and (ii) induce changes in host antibiotic susceptibility profiles. The goal of PLAS-FIGHTER is to exploit plasmid-induced physiological effects in bacteria to develop new ecology- and evolution-informed strategies against plasmid-mediated AMR. First, we will use genome-wide CRISPRi screening technology to dissect the molecular basis and functional consequences of plasmid-induced physiological effects in clinical bacteria at an unprecedented level of resolution, revealing new specific targets in AMR plasmid-carrying cells. Second, we will perform high-throughput susceptibility assays, using inhibitors of the targets revealed in the first objective and a wide range of antibiotics in a collection of paired isogenic plasmid-carrying & plasmid-free bacterial strains of the highest clinical relevance. Crucially, we will perform experiments and test candidate treatments in a gradient of increasing ecological complexity, in terms both of community composition (from monocultures to human gut communities) and habitat structure (from in vitro lab cultures to the mouse gut). In PLAS-FIGHTER, I will build on my established expertise and pioneering results to develop a novel, multidisciplinary, ground-breaking project that will open up new research avenues towards ecology- and evolution-informed anti-AMR strategies.
Wissenschaftliches Gebiet
- natural sciencesbiological sciencesmicrobiologybacteriology
- medical and health scienceshealth sciencesinfectious diseases
- natural sciencesbiological sciencesecology
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsantibiotics
- medical and health sciencesbasic medicinepharmacology and pharmacydrug resistanceantibiotic resistance
Schlüsselbegriffe
Programm/Programme
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Thema/Themen
Finanzierungsplan
HORIZON-ERC - HORIZON ERC GrantsGastgebende Einrichtung
28006 Madrid
Spanien