Pathogenic bacteria and fungi are never more resistant than when they are hunkered down behind a biofilm, a sort of armor the microbes assemble from sugar molecules. Although this armor protects microbes from immune cells and antibiotics, it may, when subjected to the right kind of assault, prove to have innumerable chinks. That’s the idea that motivated researchers from McGill University and SickKids to develop a novel enzyme technology that not only prevents the formation of biofilms, but also breaks them down.
These researchers found success by using microbes’ own tools against them. When microbes create biofilms, the researchers observed, they need to cut up and relocate sugars, activities that rely on enzymes, or rather, proteins containing glycoside hydrolase domains. The researchers found a way to use these enzymes to degrade the microbes’ sugar armor, exposing the microbes to antibiotics and host defenses.
Detailed findings appeared June 20 in the Proceedings of the National Academy of Sciences (PNAS), in an article entitled, “Microbial glycoside hydrolases as antibiofilm agents with cross-kingdom activity.” The article suggests that the scientists’ new biofilm-busting approach could be developed into treatments for a wide variety of diseases and hospital-acquired infections, such as pneumonia, as well as bloodstream and urinary tract infection. Biofilm-associated infections are responsible for thousands of deaths across North America every year.
“We demonstrate that glycoside hydrolases derived from the opportunistic fungus Aspergillus fumigatus and Gram-negative bacterium Pseudomonas aeruginosa can be exploited to disrupt preformed fungal biofilms and reduce virulence,” wrote the authors of the PNAS article. “Additionally, these glycoside hydrolases can be used to potentiate antifungal drugs by increasing their hyphal penetration, to protect human cells from fungal-induced injury, and attenuate virulence of A. fumigatus in a mouse model of invasive aspergillosis.”
This work is the result of a four-year collaboration between a McGill scientists led by Don Sheppard, M.D., and SickKids scientists led by Lynne Howell, Ph.D. “Rather than trying to develop new individual 'bullets' that target single microbes,” explained Dr. Sheppard, “we are attacking the biofilm that protects those microbes by literally tearing down the walls to expose the microbes living behind them. It's a completely new and novel strategy to tackle this issue.”
“We made these enzymes into a biofilm-destroying machine that we can use outside the microbe where the sugar molecules are found,” added co-first study author Brendan Snarr, a Ph.D. student in Dr. Sheppard's laboratory. “These enzymes chew away all of the sugar molecules in their path and don't stop until the matrix is destroyed.”
“Previous attempts to deal with biofilms have had only limited success, mostly in preventing biofilm formation. These enzymes are the first strategy that has ever been effective in eradicating mature biofilms, and that work in mouse models of infection,” noted Dr. Sheppard.
“When we took the enzymes from bacteria and applied them to the fungi, we found that they worked in the same way on the fungi biofilm; which was surprising,” commented Dr. Howell. “What's key is that this approach could be a universal way of being able to leverage the microbes' own systems for degrading biofilms. This has bigger implications across many microbes, diseases, and infections.”
“Over 70% of hospital-acquired infections are actually associated with biofilms, and we simply lack tools to treat them,” stated Dr. Sheppard. According to both lead scientists, the potential of this novel therapy is enormous and they hope to commercialize it in the coming years.