For all of the devastation that tuberculosis has caused throughout the course of human history, key portions of the bacterium responsible for this disease are remarkably fragile. Yet it is this same fragility that makes the disease so difficult to treat, providing this organism with an ability to fend off even the most powerful drugs.
Dr. Todd Lowary first encountered this paradox more than a decade ago, when he attended a lecture on the carbohydrate chemistry associated with tuberculosis. It was there that he learned about the crucial role of the polysaccharides, complex sugar chains that are the major structural component of bacterial cell walls. One of the major polysaccharides in the tuberculosis bacterium is linked to fats called mycolic acids that make the organism highly impermeable to agents that might enter and harm it.
“They’re extremely unusual structures,” he says, noting that these intricate molecules are composed of sugar rings that exist in the least stable form. Nature seldom works in this fashion, he adds, referring to the principles of thermodynamics that dictate the predominance of molecules in their lowest energy levels and the most stable molecular arrangements.
“The novelty of these structures excited me,” says Dr. Lowary, who was completing postdoctoral studies at the time. “I decided that I wanted to work in this area when I started my independent career.”
That career has seen him become an associate professor in the University of Alberta’s Department of Chemistry, and a member of the Alberta Ingenuity Centre for Carbohydrate Science, a research group that has created a critical mass of Canadian talent in this strategic field. His group applies some of the latest techniques of nuclear magnetic resonance spectroscopy, chemical synthesis and computational chemistry to examine the shape of the polysaccharides that make up the cell wall of the tuberculosis bacterium.
Soon, Dr. Lowary will begin collaborating with experts from the nearby National Institute for Nanotechnology, taking advantage of their state-of-the-art equipment for spreading these molecules on a surface for analysis. In this way, he and his group hope to identify the structural motifs that are key to the formation of the protective structure of the tuberculosis bacterium’s cell wall.
As one of six 2006 NSERC Steacie Fellows, he intends to pursue a tantalizing hypothesis about why the sugars in the polysaccharide take such an unlikely form. That form, while relatively unstable, significantly enhances the flexibility of the polysaccharide, which serves as the scaffold that attaches the mycolic acids to the cell wall.
“A more malleable scaffold would be expected to facilitate optimal packing of the mycolic acids, which provides the organism with great protection against its environment,” he says. “Even if the hypothesis turns out to be incorrect, there’ll be a lot of interesting science.”
And if the hypothesis is correct, explains Dr. Lowary, the resulting insights could unravel some of the underlying features responsible for the stubborn nature of tuberculosis. That prospect could open up entirely new avenues for addressing the disease at its most fundamental level.
“If you can make a molecule that doesn’t allow the carbohydrate coat to be produced, the organism will be more susceptible to the immune system of the human host or will be more susceptible to antibiotics, and therefore will die,” he says. “We hope that the fundamental studies we are doing will allow us to identify key residues that we can target with such compounds. This information should prove valuable in devising new therapies for the treatment of a disease of devastating human toll.”