PEAK: Plasmid Evolution and Antimicrobial resistance in Klebsiella pneumoniae

Antimicrobial resistance (AMR) is a serious threat to human health which is predicted to increase in the future. One of the most common ways that bacteria evolve resistance to antibiotics is by acquiring resistance genes; these are often carried on pieces of DNA called plasmids. Plasmids carrying resistance genes are more commonly present in clinical settings than the wider environment, and understanding this difference in prevalence is crucial for understanding the spread of resistance. However, plasmids evolve quickly and can be transferred between different types of bacteria; this makes it difficult for us to classify and track them. In PEAK, we will use new sequencing technologies and develop methods to study how plasmids evolve and transmit in the important human pathogen Klebsiella pneumoniae. We will develop new ways to group similar plasmids together and to analyse the genetic differences between these groups. We will then use these plasmid groups to study how plasmids transmit between different environments and types of Klebsiella. Finally, we will perform detailed analyses of the genetic changes that drive plasmid evolution. The aim is to use these advances to improve our ability to track AMR in Klebsiella pneumoniae and other types of bacteria.

Antimicrobial resistance (AMR) is a global threat to human health which is predicted to increase in the future. One of the most common ways that bacteria evolve resistance to antibiotics is by acquiring AMR genes; these are often carried on small pieces of DNA called plasmids. Understanding the mechanisms and conditions that promote AMR dissemination via plasmids is critical, but several knowledge gaps remain. AMR is unevenly distributed among environments, whilst the highest levels of AMR are typically found in clinical environments, the risk of AMR acquisition from environmental and animal settings remains less clear. Plasmids are important vectors for the transmission of AMR between environments, but plasmid evolution is complex, and lack of appropriate data and methods has to date largely precluded high-resolution study and surveillance of plasmids in most major pathogens. In PEAK, we will use two newly generated long-read sequencing datasets to study the evolution and transmission of plasmids and AMR genes in Klebsiella. By combining the datasets, consisting of 1594 isolates from diverse one-health sources, we will establish a unique collection of hybrid assemblies, including thousands of complete plasmids. Next, we will develop novel methods to quantify the genetic structure and diversity of plasmids. By combining this information with genetic variation in the isolate chromosomes and metadata, we will then perform phylogenetic and association analyses to disentangle AMR distributions among environments. This will enable us to identify high-risk environments for AMR transmission, followed by detailed evolutionary analyses to gain insight into the tempo and mode of plasmid evolution, and how chromosomes coevolve with plasmids. The overarching aims of PEAK are to uncover the drivers and mechanisms of the acquisition and maintenance of AMR, with the ultimate goal of enabling use of this knowledge to design interventions to combat the spread of AMR in the future.