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

Extended-spectrum cephalosporins (ESCs) are antimicrobial drugs which are used to treat serious bacterial infections such as those caused by Enterobacteriaceae, a large family of Gram-negative bacteria that includes many familiar pathogens, including Salmonella, Escherichia coli, Yersinia pestis (the cause of plague), Klebsiella and Shigella (the cause of bacterial dysentery). Resistance to ESCs in Enterobacteriaceae is a major challenge for public health worldwide. The international presence of ESC resistance in almost every ecological niche and biological compartment, including both animals and humans, makes it an ideal target to study the spread of antimicrobial resistance (AMR). This project intends to use high resolution whole genome, transcriptome, and protein data along with evolutionary 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 bacterial subtypes and their mobile genetic elements (such as plasmids) able to spread across compartments, using whole genome sequencing. A combination of analytical approaches will allow an assessment of the directionality of transmission between compartments. These analyses will be complemented by series of field experiments on the transmission of ESC resistance plasmids in two animal models (chicken and cattle), and on the effects of ESC resistance plasmids on their bacterial hosts. 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.

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 antimicrobial resistance (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.

Antimicrobial resistance (AMR) of bacterial infections is one of the greatest threats to both human and animal health. Resistance to extended-spectrum cephalosporins (ESCs) in Enterobacteriaceae is a particular concern, and is found globally. However, the relative contributions to ESC resistance from animal and human populations is still poorly understood. Our work will identify major pathways of ESC transmission between ecological niches and biological compartments and their directionality, and will have implications beyond ESCs to other antimicrobials.

The beneficiaries of this work will include national veterinary and medical policy makers in European states (including the UK) and Canada, the European Union, national farming bodies, and veterinary and medical bodies and international bodies such as the WHO and the OIE. The broad range of investigators on this project are already connected with most of these bodies and will work to ensure maximal impact of the results of this work through their ongoing activities.The identification and relative quantification of transmission pathways for ESC resistance between animals and humans that our work will provide is essential information to devise critical and evidence-based intervention points and effective strategies to control ESC resistance transmission between animals and humans. Our work and the data we generate will also be highly relevant to other researchers in the field, and we will follow standard academic means to ensure optimal dissemination of our work and results. Finally, our work on ESC resistance, AMR in general and its sources and spread has relevance to the general population, with whom we will engage through lay articles via academic advertising and communication programs.