The Science
What are biofilms?
Bacteria spend their existence cycling between two distinct modes of growth, referred to as "planktonic" and "biofilm." The mode of growth that most of the general population is familiar with is called the planktonic mode of growth. In planktonic form, bacteria exist as a single celled organism suspended in a liquid (water, blood, etc.). In this form, bacteria are exceptionally susceptible to antibiotics and our immune responses. The other mode of growth and existence for bacteria is referred to as a biofilm. A bacterial biofilm is a community of bacterial cells that are attached to a surface and are protected by an extracellular matrix. Bacterial biofilms account for >80% of all bacterial biomass on the earth. Within a biofilm state, bacteria are exceptionally hardy and they present a tremendous obstacle for intervention. Dental plaque is a prototypical example of a bacterial biofilm. Once formed, plaque (or tartar) requires mechanical and abrasive scraping to remove. This is an attribute shared by all biofilms. Bacterial biofilms require extreme countermeasures to remove once established.
The concept of a bacterial biofilm has developed slowly within the scientific community. Biofilms were arguably first studied over a century ago when plaque was scraped from human teeth and visualized under a microscope. However, the prevalence and intricacies of bacterial biofilms have been illuminated over the past 30 years. These advances were made due to crucial innovations in both high-resolution microscopy and microbiology.
Why are biofilms harmful?
Bacterial biofilms present significant obstacles in both medical and industrial settings. In the medical field, it is estimated that biofilms account for between 50-80% of microbial infections in the body and that treatments of these infections exceeds $1 billion annually in the U.S. Bacteria in a biofilm state are upwards of 10,000-fold more resistant to antibiotics and are insensitive to both antiseptic agents and host immune responses. In particular, persistent infections of indwelling medical devices (stents, catheters, pacemakers, heart valves, pins, etc.) remain a serious problem, since eradication of these infections is virtually impossible. Other diseases in which biofilms are of importance include endocarditis (inflammation of the heart lining), otitis media (ear infections), chronic prostatitis (inflammation of the prostate), periodontal disease, chronic urinary tract infections, and cystic fibrosis. In industrial settings, biofilms underpin biofouling of submerged objects, pipe corrosion, inefficiency of power plants, fouling of pulp and paper plants, bacterial spoilage of agriculture products, and the depletion of oceanic coral.
Bacteria within a biofilm state are exceptionally challenging to treat for a number of reasons. First, the extracellular matrix of the biofilm protects the bacteria from some classes of antibiotics and antiseptics, as well as immune cells. Second, bacteria within a biofilm rapidly share genetic information, leading to swift evolution of antibiotic resistance. Third, depending on the exact position of the bacteria within the extracellular matrix, the bacteria have access to different levels of nutrients and oxygen, leading to differential growth rates. This means that each bacterium expresses a different subset of proteins and is displaying a unique physiology. Some cells in biofilms, called persister cells, have entered into a dormant state and are not growing at all. Persister cells are completely resistant to antibiotics. Persister cells are particularly insidious because even if an antibiotic wipes out all of the other bacterial cells within the biofilm, the persister cells are protected from the immune response by the extracellular matrix. Therefore, once the antibiotic regimen stops, the persister cells simply repopulate the biofilm that will then disperse and infect other parts of the body. This is what leads to chronic bacterial infections.
How are biofilms currently treated?
Current approaches to controlling bacterial biofilms rely upon preventing the formation of the biofilm on the surface of interest. Two prevalent examples that illustrate the negative impact of bacterial biofilms include the fouling of ship hulls (i.e. the accumulation of algae and invertebrates) and infections of indwelling medical devices. In the shipping industry, copper-containing paint is used to impede the accumulation of algae and invertebrates on the hulls of ships. However, this process simply slows the fouling process and, more importantly, is toxic to marine life. For indwelling medical devices, ultra-sanitary precautions are followed to minimize the establishment of a biofilm colony on the indwelling medical device. However, bacteria from the skin can come in contact with and subsequently infect the device leading to chronic infection.
There are no marketed products that will disperse a pre-formed biofilm. As a result, once a biofilm is established on an inert surface, it must be removed mechanically. For example, ships must be dry docked where the hulls are physically scraped to remove all of the adhered organisms. Once a bacterial biofilm is established on an indwelling medical device, the indwelling medical device must be removed to halt chronic infection.
What is the need for dispersing biofilms?
In the medical field, molecules that disperse preformed biofilms would be significant for a number of reasons. First, they would cause bacteria to revert to a planktonic state, rendering them susceptible to both antibiotics and the immune response. This would mean that antibiotics would become more effective and those chronic infections, especially of indwelling medical devices, could be eradicated.
Second, molecules that simply cause reversion of bacterial biofilms to planktonic bacteria have no inherent risk of bacterial adaptation. Bacteria become resistant to antibiotics due to selection pressure, meaning that unless they evolve a mechanism to inactivate the antibiotic, they will be killed by the antibiotic. This places a tremendous pressure on bacteria to develop effective resistance against classes of antibiotics. Molecules that cause biofilm bacteria to revert to planktonic bacteria are not killing the bacteria; in fact they are only promoting what the bacteria do naturally (albeit at an inopportune time for the bacteria). Since bacterial death is not directly correlated with the molecule in this case, there is no inherent selection pressure to inactivate the molecule. Therefore, these molecules will potentially have an unlimited shelf life (i.e., not generate resistance).
Third, given that bacteria in biofilms are upwards of 10,000-fold more resistant to antibiotics and 50-80% of all bacterial infections are biofilm-based, molecules that disperse biofilms could be employed as adjuvant therapy to recycle old antibiotics that are no longer used due to resistance. Since molecules that disperse biofilms cause the bacteria to revert to planktonic state and are therefore more susceptible to antibiotic regimens, molecules that disperse biofilms could be employed as effective adjuvant therapy to all current antibiotics.
