Biofilms that form in the human body are up to ten thousand times more resistant to antibiotics than free-floating bacteria, making them very difficult to treat medically. These biofilms are responsible for the extreme persistence of many difficult to treat illnesses like Legionnaire’s disease, Staphylococcus aureus (“Staph”), and infectious bronchitis, that can trouble patients with frustrating symptoms for years.
Some years ago researchers showed that biofilms might also be helping the Lyme-causing bacteria evade treatment.(1) These findings have excited Lyme researchers who have since been exploring various treatment strategies designed to target the entire bacterial colony. If successful, these treatments might bring long-needed relief to patients with late-stage or persistent Lyme disease where antibiotics have previously failed.
At Bay Area Lyme Foundation, we are also inspired by these discoveries and hopeful about the treatment options they may bring. Recently we invited Daina Zeng, a Senior Scientist at Agile Sciences, to talk about the work her team is doing adapting Agile’s proprietary non-toxic organic compounds to disperse these bacterial colonies (technology they have leveraged for medical, agricultural, and industrial uses). Her post follows.
What is a biofilm?
A biofilm is something that we come into contact with every day. The plaque that forms on your teeth and causes tooth decay is a type of biofilm. Clogged drains are also caused by biofilm, and you may have encountered biofilm-coated rocks when walking into a river or stream.
Biofilms form when bacteria adhere to surfaces in some form of watery environment and begin to excrete a slimy, glue-like substance that can stick to all kinds of materials including metals, plastics, medical implant materials, and biological tissues. Biofilms can be formed by a single bacterial species or many species of bacteria, as well as fungi, algae, protozoa, debris, and corrosion products. Essentially, a biofilm may form on any surface exposed to bacteria and some amount of water.
Biofilms are thought to be responsible for more than 80% of microbial diseases, such as:
- Otitis media, the most common acute ear infection in US children
- Bacterial endocarditis, infection of the inner surface of the heart and its valves
- Cystic fibrosis, a chronic disorder resulting in increased susceptibility to serious lung infections
- Legionnaire’s disease, an acute respiratory infection resulting from the aspiration of clumps of Legionnella biofilms detached from air and water heating/cooling and distribution systems
- Chronic wounds (wounds that do not heal within three months)
- Hospital-acquired infections, such as infections acquired from the surfaces of catheters, medical implants, wound dressing, or other medical devices
How might a biofilm explain the persistence of Lyme?
Forming a biofilm is a very effective protective mechanism and bacteria encased in a biofilm are highly resistant to antibiotics (up to 10,000-fold). So antibiotic treatment is often times not effective against cells protected in a biofilm. Unfortunately, cells within a biofilm can return to their freeliving form and escape to form new biofilms and/or colonize new tissues. Since antibiotics can’t be continuously given to a patient, there really isn’t anything to stop these bacteria cells from spreading the disease. It’s really a vicious cycle.
What has the research actually shown regarding Lyme disease and biofilms? What is the importance of some of the more recent studies?
Even though biofilms have been attributed as one of the underlying causes that make other chronic bacterial infections so difficult to treat, (such as cystic fibrosis, chronic wounds, endocarditis, etc.), biofilms have not been well studied in Lyme disease. There are papers showing that Borrelia burgdorferi, the causative agent of Lyme disease, forms biofilms outside of a host (in vitro).
Current studies are being done to probe the presence of biofilms in animal models and even human patient biopsy samples. We look forward to the results of those studies that should be coming out in the next year or so.
These studies are very important since they increase our understanding of Borrelia burgdorferi; and given that biofilms are so prevalent and relevant in other pathogens, it’s worthwhile to study whether biofilms play a role in Lyme disease as well.
Is it possible that the antibiotics might actually trigger the biofilms to create a stronger barrier?
Absolutely! Biofilm is a protective mechanism that cells turn on when they sense they’re under stress, so there’s significantly more biofilm formation when cells are treated with antimicrobial agents including antibiotics. Numerous studies have shown this for nearly all antibiotics.
To what extent does it mask the Lyme bacteria from detection?
Since bacteria are encased in a biofilm and are not free-swimming in solution, they can be hard to detect using diagnostic tests that rely on solution samples (i.e. blood, etc).
What can be done to combat the biofilms?
The only way to effectively combat a biofilm is to “pop the bubble” and disperse it. There are two major ways to do that: (1) using mechanical force to scrape it off (similar to a teeth cleaning), or (2) tricking the cells into dispersing themselves. Since Lyme disease is within the body, it’s not possible to use mechanical force. So the only available tool left is to use chemical compounds that inhibit the ability of cells to form and maintain biofilms.
At Agile Sciences, we have developed compounds that inhibit bacteria’s ability to turn on the pathways required for biofilm formation. So when we treat bacteria with our compounds, we see significantly less biofilm formation, and we’re also able to disperse existing biofilms. We think the best use of these compounds is in combination with antibiotics. The idea would be for our compound to “pop” the biofilm so the antibiotic could now kill the pathogen.
Support from Bay Area Lyme Foundation has allowed us to identify compounds (known as Agilyte®) that have efficacy against Borrelia burgdorferi biofilms and show synergy with commonly used antibiotics in Lyme disease, including doxycycline (see Figure below), ceftriaxone, and amoxicillin. We’re currently applying for further funding from NIH to develop these compounds as a novel therapeutic to enhance antibiotic treatment of Lyme disease. See here for more information about the Agile project.
What new research might help advance this line of treatment?
At the end of the day, I really do believe we need to have a further understanding of how Borrelia acts in the human body and whether they form biofilms. Since biofilms are so prevalent and increasingly implicated in more and more diseases, I think it’s important to study if it plays a role in Lyme disease.
On our end, we’re working on getting funding that will allow us to take our compounds into animals to see if using our compound can enhance doxycycline treatment in mice.
(1) Sapi et al. “Characterization of biofilm formation by Borrelia burgdorferi in vitro.” PLOS One, 2012: 7 (10).
(2) Monroe, D., “Looking for Chinks in the Armor of Bacterial Biofilms,” PLoS Biology, Vol. 5, No. 11, e307 doi:10.1371/journal.pbio.0050307
Images courtesy of Monroe (Stages of Biofilm Development), Sapi et al. (Borrelia burgdorferi biofilm), and Zeng (Agilyte® Technology).