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Analysing the role of history, chance and selection on the evolution of plasmid-mediated antibiotic resistance
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 ev...
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.
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Duración del proyecto: 25 meses
Fecha Inicio: 2020-09-01
Fecha Fin: 2022-10-31
Fecha Fin: 2022-10-31
Línea de financiación: concedida
El organismo H2020 notifico la concesión del proyecto el día 2022-10-31
H2020
No se conoce la línea exacta de financiación, pero conocemos el organismo encargado de la revisión del proyecto.
Presupuesto
El presupuesto total del proyecto asciende a
173K€
Líder del proyecto
FUNDACION PARA LA INVESTIGACION BIOMEDICA DEL...
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