Bio sciences team targets deadly super bug

Scientists look to break structural code of virus

By Natalie St-Denis

very researcher dreams of a breakthrough. Dr. Ken Ng along with his team members Dr. Jason Ho, a post-doctoral fellow, and Antonio Greco, a lab technician, are hopeful they will soon hold the key to the first step in creating a new treatment for a deadly bacterium found in hospitals across Canada. Clostridium difficile is a super bug that has been extremely difficult to treat.

“Hospital patients on antibiotics are susceptible to contracting this infection, which can lead to severe diarrhea and damage the intestine. It’s potentially deadly given that patients are often weak to begin with. And at this time, there really isn’t a good treatment for it,” says Ng (left), assistant professor at U of C’s Department of Biological Sciences. There were at least 83 deaths in Montreal and Calgary between the latter part of 2003 and the first half of 2004. Precise numbers are hard to establish as many hospitals are unwilling to release this information.

Ng is part is part of a six member multi-disciplinary team formed through the Alberta Ingenuity Centre for Carbohydrate Science. Chemists, biochemists and biologists are working together and using the novel structure-based drug design approach to create new drug treatments. Ng’s role in the process is to identify the shape and structure of key proteins involved in bacterial and viral infections.

By using a technique called X-ray crystallo-graphy, Ng is able to come up with a computer model of the molecular structure of important proteins. The model is the first step in creating a drug that will then fit into the grooves and bumps of the proteins, just like two pieces of a puzzle coming together, blocking the protein’s normal activities.

But this doesn’t happen overnight. X-ray crystallography is a lengthy and involved process that requires scientists to grow crystals by incubating purified protein extracts in hundreds to thousands of different crystallization trials and then observe these for up to several weeks.

After obtaining large and well-ordered crystals, high-powered X-rays are aimed at these crystals.

By measuring the ways in which the rays scatter and diffract from the crystal, a three-dimensional image of the molecular structure is then computed based on that information.

After two years of work, Ng and his collaborators are on the verge of breaking the structural code of a key toxin produced by the super bug. Once this step is achieved, the process of developing a novel treatment will be possible.

“ The structure-based drug approach has the potential to shorten the time and reduce the cost of creating new drugs compared to the traditional trial-and-error drug development process,” says Ng.

This is where the talented multi-disciplinary team comes in.

Chemists David Bundle, Monica Palcic and Todd Lowary at the University of Alberta are providing a wide array of chemically synthesized carbohydrates to test as lead drug candidates. Biochemists David Schriemer and Glen Armstrong at the U of C are screening libraries of potential drug candidates and testing their efficacy in cell culture and animal model systems.

“ The Alberta Ingenuity Centre provides a unique opportunity for a close-knit group of basic science researchers to pursue a more complex and ambitious project requiring a wide range of complementary expertise,” says Ng. Other funding agencies involved include AI, AHFMR, CFI, NSERC and CHIR.

Ng and his collaborators are also attempting to unveil the secret structure of the key reproductive enzyme in a family of well-known viruses that include the SARS coronavirus, the West Nile virus, Hepatitis C and the Norwalk virus.

“ We are using basic biochemical studies to understand the fundamentals important to the reproduction of these viruses.

“ It is the beginning of a long journey that may take more than a decade before a clinically useful drug appears on the market. Although it is discouraging that it takes so long to see the fruits of our efforts, we hope our work will lead to new and better treatments for very serious diseases,” says Ng.