By examining the whole genome sequences of around two thousand resistant bacteria, predominantly Escherichia coli collected between 2008 and 2016, the team found that different types of AMR genes varied in their temporal dynamics. For example, some were initially found in North America and spread to Europe, while for others the spread was from Europe to North America.
Not only did the study look at bacteria from different geographic regions but also from diverse hosts including humans, animals, food (meat) and the environment (wastewater), to define how these separate but interconnected factors influenced the development and spread of AMR. Understanding this interconnectivity embodies the One Health approach and is vital for understanding transmission dynamics and the mechanisms by which resistance genes are transmitted.
The study was supported by the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR), a global collaboration spanning 29 countries and the European Commission that is tasked with turning the tide on AMR. Without concerted efforts on a global scale, AMR will undoubtedly make millions more people vulnerable to infections from bacteria and other microorganisms that can currently be tackled with antimicrobials.
The team focussed on resistance to one particularly important group of antimicrobials, the Extended-Spectrum Cephalosporins (ESCs). These antimicrobials have been classed as critically important by the World Health Organization because they are a ‘last resort’ treatment for multidrug resistant bacteria; despite this, since their introduction, efficacy has declined as bacteria have developed resistance.
Bacteria that are resistant to ESCs achieve this through the production of specific enzymes, called beta-lactamases, that are able to inactivate ESCs.
The instructions for making these enzymes are encoded in genes, particularly two key types of genes: extended-spectrum beta-lactamases (ESBLs), and AmpC beta-lactamases (AmpCs).
These genes may be found on the chromosomes of bacteria where they are passed to progeny during clonal multiplication, or in plasmids, which are small DNA molecules separate to the bacterium’s main chromosome. Plasmids are mobile and can move directly between individual bacteria representing an alternative way of exchanging genetic material.
This study identified how some resistance genes proliferated through clonal expansion of particularly successful bacterial subtypes while others were transferred directly on epidemic plasmids across different hosts and countries.
Understanding the flow of genetic information within and between bacterial populations is key to understanding AMR transmission and the global spread of resistance. This knowledge will contribute to the design of vitally needed interventions that can halt AMR in the real world where bacteria from diverse hosts and environmental niches interact, and where international travel and trade mean that these interactions are not limited by geography.
Professor Alison Mather, group leader at the Quadram Institute and the University of East Anglia, said: “By assembling such a large and diverse collection of genomes, we were able to identify the key genes conferring resistance to these critically important drugs. We were also able to show that the majority of resistance to extended spectrum cephalosporins is spread by only a limited number of predominant plasmids and bacterial lineages; understanding the mechanisms of transmission is key to the design of interventions to reduce the spread of AMR”.
Lead author Dr Roxana Zamudio said “Antimicrobial resistance is a global problem, and it is only by working collaboratively with partners in multiple countries that we can get a holistic understanding of where and how AMR is spreading”.
This project was supported by the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR), through the Medical Research Council (MRC, MR/R000948/1), the Canadian Institutes of Health Research (CFC-150770), and the Genomics Research and Development Initiative (Government of Canada), the German Federal Ministry of Education and Research (BMBF) grant no. 01KI1709, the French Agency for food environmental and occupational health & safety (Anses), and the French National Reference Center (CNR) for antimicrobial resistance. Support was also provided by the Biotechnology and Biological Sciences Research Council (BBSRC) through the BBSRC Institute Strategic Programme Microbes in the Food Chain BB/R012504/1 and its constituent project BBS/E/F/000PR10348 (Theme 1, Epidemiology and Evolution of Pathogens in the Food Chain)