In collaboration with colleagues across the Government of Canada, researchers at the Public Health Agency of Canada (PHAC) are developing genomics‑based tools to better track and understand how antimicrobial resistance (AMR) circulates among humans, food production and the environment—one of a series of closely coordinated research projects underway at 5 departments and agencies under the federal Genomics Research and Development Initiative Antimicrobial Resistance project (GRDI‑AMR).
New genomics technologies changing the game
"…traditional methods involved a lot of time‑consuming, hands‑on work in the lab…With whole genome sequencing we can simultaneously predict whether a bacteria is likely to be resistant to a particular antibiotic and identify the genes involved…"
The PHAC research involves 4 sub‑projects, co‑led by Research Scientist Dr. Ed Taboada, who says technologies such as whole genome sequencing (WGS)—acquired through GRDI funding—have added a new dimension to AMR research in Canada.
"The traditional methods involved a lot of time‑consuming, hands‑on work in the lab—collecting samples of bacteria from different places, a poultry operation or a retail store, for example, extracting bugs of interest from those, testing them for AMR by growing them in the presence of a number of antibiotics—and then sending them off to another lab for DNA fingerprinting," says Dr. Taboada. "After all that, the information wasn't detailed enough to allow you to draw any definite conclusions—you couldn't be sure that you were looking at the same strain of the bacteria, let alone whether they carried the same AMR genes."
"With whole genome sequencing we can simultaneously predict whether a bacteria is likely to be resistant to a particular antibiotic and identify the genes involved—plus it gives you a really high‑resolution molecular fingerprint so you can say with a lot of confidence that, yes, it's the same bacteria and the same genetic resistance to this or that antibiotic."
Extra layers of knowledge
The level of detail revealed by WGS technology is truly remarkable. "We can see, for example, not only that a particular bug is resistant to penicillin, but also exactly which of the many genes that provide resistance to penicillin it has," says Dr. Taboada. "On top of that, WGS lets us see whether that AMR gene is contained in something called a plasmid—which can carry genes from one species of bacteria to another—so we can say, 'okay, in terms of spreading AMR, this bacteria is a high risk'."
Bringing it all together
As part of the GRDI‑AMR project, federal researchers are using WGS to assemble detailed genomic profiles of literally thousands of bacterial isolates collected from a variety of environments and by different agencies over a number of years—which amounts to millions of pieces of data that need to be managed and analysed. That is where the PHAC research Dr. Taboada leads with his colleague Dr. Gary Van Domselaar comes in.
"You can imagine trying to sort through that much data manually," says Dr. Taboada. "So we have 4 different teams working on bioinformatics software and other computing tools we need to make use of all this information—to identify which bacteria have AMR, which AMR genes they have and everything else we know about them, including when and where they were collected."
"…we have four different teams working on bioinformatics software and other computing tools we need to make use of all this information—to identify which bacteria have AMR, which AMR genes they have and everything else we know about them, including when and where they were collected."
Based on analysis of the data, researchers are bringing a new clarity to our understanding of how AMR can be transmitted, in particular, the role played by plasmids. "Because of their ability to carry genes from one species of bacteria to another, they are a real risk in terms of spreading AMR," says Dr. Taboada. "In developing the bioinformatics tools to predict where plasmids will occur—and how they will behave—GRDI‑AMR researchers have taken a significant step forward."
Adding value, extending collaboration
The software developed by PHAC researchers has already been adopted as a central component of the Antimicrobial Resistance: Emergence, Transmission, and Ecology project—ARETE—a new research effort funded by Genome Canada.
At Dalhousie University in Halifax, ARETE lead investigator Dr. Robert Beiko says the ultimate goal of the project is to pinpoint potential "hotspots" of AMR transmission between different types of habitat, and different isolates and species of pathogen. Along with researchers from McMaster and Simon Fraser universities, ARETE includes a team from PHAC contributing the bioinformatics expertise and genomic datasets generated as part of the GRDI‑AMR project.
Dr. Beiko says the GRDI‑AMR research is a key part of ARETE. "Along with leading‑edge software to help identify key determinants of AMR, the work on environmental connections between isolates gives us a way to identify gene transmission across habitat boundaries," says Dr. Beiko. "On top of those, the genomic datasets will act as a proving ground to validate the tools we are developing."