Descripción del proyecto
Resistencia antimicrobiana: evolución y gestión
El uso indebido de antibióticos ha provocado el desarrollo de resistencia antimicrobiana (RAM) en las bacterias. En las bacterias, los genes de RAM se transfieren de forma horizontal a través de elementos genéticos móviles como los plásmidos y permiten a las bacterias sobrevivir a los antibióticos. Sin embargo, investigaciones recientes han descubierto que los plásmidos de RAM también inducen cambios en la fisiología de la célula hospedadora bacteriana y en la susceptibilidad a los antibióticos. El equipo del proyecto PLAS-FIGHTER, financiado por el Consejo Europeo de Investigación, pretende desarrollar nuevas estrategias contra la RAM mediada por plásmidos a partir de la identificación de dianas específicas en las células portadoras de plásmidos y el ensayo de inhibidores de estas dianas en una amplia gama de cepas bacterianas en condiciones ecológicas variables. Este método multidisciplinar contribuirá al desarrollo de nuevas estrategias contra la RAM.
Objetivo
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.
Ámbito científico
- 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
Palabras clave
Programa(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Régimen de financiación
HORIZON-ERC - HORIZON ERC GrantsInstitución de acogida
28006 Madrid
España