By Jennifer Doucet & Anushka Jayasuriya – June 23, 2017
Microbes, including bacteria and fungi, have many tools to evade a host cell’s defenses and antimicrobial therapies. One tool is the creation of protective barriers called biofilms, made of proteins, DNA, and sugar polymers, which spread across surfaces and impede immune system responses and antimicrobial treatments. In fact, biofilms can make microbes up to 1000 times more resistant to treatment. Despite their critical role in resistance to antimicrobials, there are no currently licensed therapies that target mature biofilms.
The bacteria Pseudomonas aeruginosa and the fungus Aspergillus fumigatus both form sugar-rich biofilms in host tissues during infection. They cause serious infections worldwide, especially in immunocompromised patients or those with chronic disease. Additionally, co-colonization by both P. aeruginosa et A. fumigatus has been observed in patients with lung disease such as cystic fibrosis.
As recently published in the Proceedings of the National Academy of Sciences (PNAS) journal, a team led by GlycoNet investigators Drs. Donald Sheppard and Lynne Howell have identified glycosyl hydrolases, a class of enzymes that modulate the removal of sugar residues, as prime targets in combating biofilm formation. The team cloned and expressed glycosyl hydrolase domains from both P. aeruginosa et A. fumigatus in order to test their ability to disrupt pre-formed biofilms and prevent biofilm formation. Lab results confirmed that glycosyl hydrolase treatment led to degradation and prevention of biofilms, reduced virulence, and increased response to antimicrobial therapeutics. Specifically, they enhanced the activity of antifungals by breaking down the biofilm, which allowed the antifungals to penetrate the cell wall. Glycosyl hydrolases were also non-cytotoxic and well tolerated in mice, further supporting them being a promising therapeutic candidate.
“We were able to use the microbe’s own tools against them to attack and destroy the sugar molecules that hold the biofilm together,” said Dr. Sheppard. “Rather than trying to develop new individual ‘bullets’ that target single microbes 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.”
In addition, as each organism produces similar glycan structures to form biofilms, the team hypothesized that the glycosyl hydrolases would exhibit cross-species activity. Excitingly, bacterial hydrolase enzymes were equally active against fungal biofilms, suggesting that some of these enzymes may be useful therapeutic agents in cases of co-colonization, such as in cystic fibrosis patients, as well as for a wide range of microbes.
“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,” explained Dr. Howell.
Future research will include more detailed toxicity and pharmacokinetic studies, as well as testing of these agents alone and in combination against established fungal infections.
To read the full paper, click ici..