Enhancing Canada's Preparedness to Deal Wtih Emerging Infectious Diseases

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By Shawn Lawrence

The skin infection known as the ‘Staph’ has been around for as long as medicine has been practiced. With the introduction of antibiotics in the 1940’s and 50’s, the ‘Staph’ was treatable and quite sensitive to penicillin. That all changed just a few decades later when a new strain of ‘Staph’ emerged, dubbed methicillin-resistant Staphylococcus aureus (MRSA). This new strain proved more resistant to modern drugs and first line antibiotics. Now the dreaded superbug has made a comeback, becoming the scourge of hospitals on both sides of the 49th parallel.

Most common in hospitals and other institutional health-care settings, MRSA tends to strike older people and those with weakened immune systems. Skin-to-skin contact, cuts or abrasions of the skin, contaminated items and surfaces, crowded living conditions and poor hygiene have all been associated to the spread of the pathogen and the fact it can live for up to 24 hours on just about any surface is also a contributing factor to its spread.

Led by provincial executive director of the BC Centre for Disease Control, Dr. Robert Brunham and co-principal investigators Brett Finlay professor in the Michael Smith Laboratories, and the Departments of Biochemistry and Molecular Biology, and Microbiology and Immunology at the University of British Columbia and Neil Reiner, Head of the Division of Infectious Diseases at Vancouver General Hospital and UBC Department of Medicine; and funded by Genome BC and Genome Canada and supported by a talented team of researchers from the University of British Columbia (UBC), Vancouver General Hospital (VGH), and the BC Centre for Disease Control (BC CDC), the PREPARE (PRoteomics for Emerging Pathogen Response) project is a collaborative initiative that is using cutting edge science to tackle MRSA head on.

Through the use of molecular microbiology, proteomics and computer aided drug design, the goals of the PREPARE project are to identify novel microbial drug and vaccine targets through the study of protein interaction networks; to create key research linkages and infrastructure to enhance Canada ‘s preparedness for emerging infectious diseases and to develop new research technologies for creating new products (drugs and vaccines) for emerging infectious diseases. In addition to MRSA, three other super pests: Salmonella, E. coli and Chlamydia have also been targeted by the project. However, MRSA remains the project’s highest priority and an area in which PREPARE has made its most significant strides.

“It (MRSA) is a critical problem in our public health system, one which we are seeing increasingly more everyday in the wards of our hospitals, so the need to address it or do more to stop it has never been greater,” explained Dr. Reiner.

Backing Reiner’s assertion, the Centers for Disease Control and Prevention (CDC) estimates that nearly 95,000 Americans developed MRSA infections with close to 19,000 MRSA deaths reported in 2005 alone. The economic cost reported by the CDC was in the $3 billion range. In Canada managing one patient with MRSA can cost anywhere from $17,000 to $35,000 according to the Association of Medical Microbiology and Infectious Disease Canada.

The first step taken by PREPARE to overcome MRSA is to identify novel drug targets within the MRSA pathogen, while understanding the architecture of protein interaction networks within MRSA cells and how the cells function. Using proteomics, bioinformatics and in sillico (computer modeling) drug design, the PREPARE team is able to best map out these interactions and understand how MRSA proteins interact.

Over the past decade or so it has been generally determined through experimentation that the organization of proteins in all living cells is not a random occurrence and this is a fact that bodes well for PREPARE’s research as it relates to MRSA “It’s highly ordered in the sense that the there are specific patterns of interactions between individual proteins. For example, if you take a bacteria that has 2,500 genes with say for example a corresponding number of proteins, within those genes there are a set number of proteins that have a much higher degree of connectivity. The reason this is important is that these proteins with the highest degree of connectivity are also crucial to cell function. As such, if you disrupt them, you can actually destabilize the network and kill the cell with a higher degree of predictability,” said Reiner.

For this reason, understanding the architecture of protein interactions within living cells is critical he explained and is why the PREPARE team has focused its efforts on identifying the proteins with high connectivity or “hubs” as they are commonly referred to as vulnerable targets in pathogens like MRSA.
“Essentially we’re studying the protein interaction network in pathogens such as MRSA and focusing upon this hierarchy of connectivity specifically on the proteins that are very highly connected for the purpose of targeting them with drugs and compounds that function effectively as antibiotics. In other words opening the door for new drugs that will “knock out” the proteins and kill the microbes.”

Tremendous progress has already been made in finding novel targets in MRSA with the PREPARE team identifying approximately 30-40 new drug target candidates, while some proteins in MRSA have been found to have 400-500 connections with other proteins. “We’re not even halfway through the project yet and we expect many more targets to emerge,” he said.

Moreover validation and proof of principle is expected to be completed within a two year time frame. Such an accomplishment, according to Reiner, is a significant step towards not just finding a treatment for MRSA but also translating the group’s findings and applying them to other pathogens thus strengthening Canada’s preparedness against other emerging pathogens that pose a risk. This has lead to some very exciting and potentially exploitable data that could one day lead to development of drugs and vaccines for MRSA and possibly other pathogens. Still at this juncture, Reiner is cautious about the progress made and considers the timing premature to celebrate.

“The end hope is that we will be able to create a research platform through achieving a better understanding of existing pathogens like MRSA, which we can then set back into motion whenever a new, emerging disease is identified as a threat.”

Likewise, PREPARE hopes to make similar advancements with pathogens like Salmonella, E. Coli and Chlamydia that they are also tackling at the bench. The choice of these three pathogens has much to do with significant amount of experience and a track record of the team in dealing with them and because they are also major human pathogens.

While the bench research is important as it pertains to the project, advancements being made away from the bench by one of the team members using bioinformatics and in sillico to scan the genomes on a large number of other pathogens and modeling pathogens through computer based work are just as integral. Findings with these organisms that emerge will allow the team to redeploy its platform in response and could result in new projects and further creation of new drugs and vaccines. Most importantly it will allow for the preparation for other emerging pathogens at a faster pace.

“We are taking some significant steps with the work we are doing, we’re not in drug development, but we are coming up with lead compounds, creating new opportunities and discoveries that at some stage down the line industry can take forward,” said Reiner.