Genomic approach to transmission and compartmentalization of extended-spectrum cephalosporin resistance in Enterobacteriaceae from animals and humans




Research Project: 2017-05-01 - 2020-04-30
Total sum awarded: €1 534 823

Resistance to extended-spectrum cephalosporins (ESC) in Enterobacteriaceae is a major challenge for public health worldwide. Its international presence in almost every ecological niche and biological compartment with still ongoing dynamic expansion makes it an ideal target to study the spread of AMR. This project intends to use genomic, evolutionary, transcriptomics, proteomics and experimental approaches to assess the similarities between a variety of ecological niches and biological compartments formed by Enterobacteriaceae species, host species/source (humans, dogs, cattle, swine, chicken, meat products) and geography (Europe: Germany and France, and North America: Canada). These similarities will serve as a basis to identify and focus further on clonal lineages and plasmids able to spread across compartments, using whole genome and plasmid sequencing. A combination of phylogenetic and epidemiologic analyses will allow an assessment of the directionality of transmission between compartments. These analyses will be complemented by series of experiments on transmission of ESC resistance plasmids in vivo in two animal models (chicken and cattle) and on effects of ESC resistance plasmids on the bacterial transcriptome and proteome and its association with plasmid maintenance. These experiments will help to identify major transmission pathways between animals and humans and potential new intervention targets for the control of ESC resistance. The team assembled for this project consists of experienced researchers with a wide spectrum of expertise ideal for the successful completion of a study of antimicrobial resistance in the context of One Health.

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  • Patrick Boerlin, University of Guelph, Canada (Coordinator)
  • Richard Bonnet, Université Clermont Auvergne, France (Partner)
  • Jean-Yves Madec, ANSES, French Agency for Food, Environmental and Occupational Health & Safety, France (Partner)
  • Michael Mulvey, University of Manitoba, Canada (Partner)
  • Stefan Schwarz, Friedrich-Loeffler-Institut, Germany (Partner)
  • James Wood, University of Cambridge, United Kingdom (Partner)
  • Alison Mather, Quadram Institute Bioscience, United Kingdom (Observer)
  • Heike Kaspar, Federal Office of Consumer Protection and Food Safety, Germany (Observer)

This project studied the epidemiology of resistance to a critically important group of antibiotics called extended-spectrum cephalosporins (ESCs) in humans, animals and food. It showed that the multiplication, transmission and host adaptation of major bacterial strains such as the famous E. coli ST131 is only one method by which resistance to ESCs spreads. The study has identified specific types of ESC resistance plasmids (genetic elements which can move from one bacterium to another), which are spreading very actively in bacterial populations from humans and animals (including wildlife), from the local to the international level and even between Europe and North America. By comparing bacteria with and without ESC-resistance plasmids the researchers have discovered new interactions between plasmids and their host bacterium. In one case, these interactions may be associated with the regulation of chromosomal genes by plasmid genes not related to antimicrobial resistance. In another case, an antimicrobial resistance gene (mcr) other than for ESC but frequently located on the same plasmid was shown to facilitate the establishment and colonization of the gut by bacteria. In both cases, these interactions are thought to increase the success of ESC resistance plasmids in bacterial populations. Finally, the researchers also showed that the use of antimicrobials increases the persistence of ESC-resistant bacteria in cattle. They developed mathematical models which allow to predict and quantify this effect. Overall, this study has generated new information on the epidemiology of ESC resistance and mathematical models which will be of great use for both scientists and policy makers in the fight against antimicrobial resistance.