Descripción del proyecto
Estudio de la evolución de la resistencia a los antimicrobianos
La evolución de los caracteres en una población determinada se rige por tres fuerzas: la historia, el azar y la selección. En lo que respecta a la resistencia a los antimicrobianos (RAM), aunque la transferencia horizontal de genes es la ruta principal para su propagación en patógenos bacterianos, los indicios proporcionados por hospitales de todo el mundo demuestran que la historia y el azar limitan su aparición. El objetivo del proyecto financiado con fondos europeos REPLAY es investigar la evolución de la RAM mediada por plásmidos en cepas clínicas de «Klebsiella pneumoniae». Los investigadores emplearán técnicas de evolución experimental y la secuenciación del genoma completo para estudiar cada fuerza evolutiva. Teniendo en cuenta el reto médico que plantea la RAM, los resultados mejorarán nuestra capacidad de predecir la evolución de la RAM y diseñar nuevas estrategias de tratamiento.
Objetivo
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.
Ámbito científico
- 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
Palabras clave
Programa(s)
Régimen de financiación
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinador
28034 Madrid
España