Description du projet
Étudier l’évolution de la résistance aux antimicrobiens
L’évolution des traits d’une population donnée est gouvernée par trois forces: l’histoire, le hasard et la sélection. En ce qui concerne la résistance aux antimicrobiens (RAM), même si le transfert horizontal des gènes constitue la voie principale de propagation parmi les agents pathogènes bactériens, des preuves issues d’hôpitaux du monde entier montrent que l’histoire et le hasard contraignent son émergence. Le projet REPLAY, financé par l’UE, cherche à étudier l’évolution de la RAM plasmidique chez des souches cliniques de Klebsiella pneumoniae. Les chercheurs utiliseront des techniques d’évolution expérimentale et le séquençage du génome entier pour étudier chaque force évolutive. Compte tenu du défi médical posé par la RAM, les résultats amélioreront notre capacité à prédire son évolution et à concevoir de nouvelles stratégies d’intervention.
Objectif
Antimicrobial resistance (AMR) in bacteria is one of the main challenges faced by modern medicine and understanding its evolution is urgently required. As any other evolved trait, three fundamental evolutionary forces guide the evolution of AMR: history, chance and selection. The specific role of each force determines whether, by what mechanism, and to what degree AMR evolves in a given population. Horizontal gene transfer is the main route for acquisition of AMR in bacterial pathogens and plasmids play a key role in the spread of resistant determinants. Of critical clinical importance is plasmid-mediated carbapenem-resistance in the Enterobacteriaceae family. The recurrent isolation of certain successful plasmid/bacterium associations in hospitals distributed worldwide is an example of how history and chance constrain the emergence of AMR. For example, pOXA-48 plasmid, encoding the OXA-48 carbapenemase, is frequently associated with the ST11 serotype of Klebsiella in hospitals around the world. Why is pOXA-48 restricted to a handful of clones if it can be mobilized to all K. pneumoniae serotypes? To answer this question, I am proposing a novel project that will analyze the impact of the three evolutionary forces in the evolution of plasmid-mediated AMR in clinical strains of K. pneumoniae. First, using experimental evolution and whole genome sequencing, I will quantitatively analyze the impact of each evolutionary force in AMR evolution. Also, I will study the adaptive mutational pathways leading to the compensation of plasmid-mediated costs. Then, I will use the novel high-throughput genetic screen CRISPRi, which allows silencing the expression of all chromosomal and plasmid genes one by one, to analyze the molecular basis determining the successful plasmid/bacterium associations. Altogether this cutting-edge proposal will greatly impact our ability to predict AMR evolution, paving the way for the development new intervention strategies to counteract AMR.
Champ scientifique
- medical and health sciencesmedical biotechnologygenetic engineeringgene therapy
- natural sciencesbiological sciencesmicrobiologybacteriology
- humanitieshistory and archaeologyhistory
- natural sciencesbiological sciencesevolutionary biology
- medical and health sciencesbasic medicinepharmacology and pharmacydrug resistanceantibiotic resistance
Programme(s)
Régime de financement
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinateur
28034 Madrid
Espagne