Descrizione del progetto
Resistenza antimicrobica: evoluzione e manipolazione
L’abuso di antibiotici ha portato allo sviluppo della resistenza antimicrobica (AMR, AntiMicrobial Resistance) nei batteri. I geni della resistenza antimicrobica vengono trasferiti orizzontalmente nei batteri attraverso elementi genetici mobili come i plasmidi e consentono ai batteri di sopravvivere agli antibiotici. Tuttavia, alcune recenti ricerche hanno scoperto che i plasmidi AMR inducono anche cambiamenti nella fisiologia della cellula batterica ospite e nella sensibilità agli antibiotici. Finanziato dal Consiglio europeo della ricerca, il progetto PLAS-FIGHTER mira a sviluppare nuove strategie contro la resistenza antimicrobica mediata da plasmidi, identificando bersagli specifici nelle cellule portatrici di plasmidi e testando inibitori di questi bersagli in un’ampia gamma di ceppi batterici in condizioni ecologiche diverse. Questo approccio multidisciplinare contribuirà allo sviluppo di nuove strategie contro l’AMR.
Obiettivo
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.
Campo scientifico
- 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
Parole chiave
Programma(i)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Argomento(i)
Meccanismo di finanziamento
HORIZON-ERC - HORIZON ERC GrantsIstituzione ospitante
28006 Madrid
Spagna