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Analysing the role of history, chance and selection on the evolution of plasmid-mediated antibiotic resistance

Project description

Investigating the evolution of antimicrobial resistance

The evolution of traits in any given population is governed by three forces: history, chance and selection. With regard to antimicrobial resistance (AMR), although horizontal gene transfer is the main route for its spread in bacterial pathogens, evidence from hospitals worldwide demonstrates that history and chance constrain its emergence. The scope of the EU-funded REPLAY project is to investigate the evolution of plasmid-mediated AMR in clinical strains of Klebsiella pneumoniae. Researchers will employ experimental evolutionary techniques and whole genome sequencing to study each evolution force. Considering the medical challenge posed by AMR, results will improve our ability to predict AMR evolution and design new intervention strategies.


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.


Net EU contribution
€ 172 932,48
Ctra colmenar vlejo km 9.100
28034 Madrid

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Comunidad de Madrid Comunidad de Madrid Madrid
Activity type
Other funding
€ 0,00