Bacteriophages
Bacteriophages (phages) are viruses that only infect their host bacteria.
Bacteriophage has specialized absorption structures, which bind specific receptors on the host bacteria. This specific binding gives most phages a very narrow host range, which is usually just a small subpopulation (strain) of a particular species of bacteria.
Once the absorption takes place, the phage is able to inject its genetic material into the host bacteria. A transition then takes place by which the phage derived genetic material takes over the host’s metabolic systems and reproduces phage components. The different parts of the phage are then assembled into whole functional phages.
There are a few studies looking at the ability of bacteriophage to infect host bacteria residing in a biofilm phenotype. Several studies in controlled laboratory settings have demonstrated phage can absorb, replicate and reinfect their host bacteria within a biofilm structure.
Specific phage products such as polysaccharide depolymerase have been identified, and have been observed to degrade the host bacterium’s EPS material (extracellular polymeric substances). However, the EPS material produced by a particular bacterium changes based on substrates and interactions with other bacterium in the biofilm. So it is unclear in a clinical setting how effective phage will be against biofilm.
Two points need to be made in defense of the use of bacteriophage in treating biofilm-based diseases.
-First, there are an estimated 10^31 bacteriophages worldwide. This makes bacteriophages a highly successful “life form” whose only food source is their host bacteria. Bacteria in natural environments overwhelmingly choose to live in an organized biofilm. Therefore, bacteriophages must have some natural success infecting biofilms.
-Second, there seems to be a significant clinical success in treating biofilm-based diseases such as sinusitis, osteomyelitis, wounds and other infections with bacteriophages.
In an over 60-year history in using bacteriophages clinically, there have been multiple clinical studies and case reports suggesting the efficacy of bacteriophage in biofilm infections. Although there is no controlled randomized study to date, clinical evidence suggests that bacteriophage is indeed effective against biofilms.
The use of bacteriophage in the management of chronic wounds has several advantages. Bacteriophage is specific for its particular host, will amplify itself indefinitely as long as the host bacteria is available and requires lysis (death) of the bacterium. Also, bacteriophage is extremely safe with no significant adverse events reported in human use.
Two disadvantages of bacteriophage have limited its use in therapy.
-First, bacteriophage’s narrow host spectrum requires a number of different individual phages against a particular species (example: P. aeruginosa). And even with phage cocktails, that is, polyvalent phage mixtures, there are still gaps in the treatment spectrum. For example, in P. aeruginosa a standard phage cocktail, (polyvalent phage) will cover only about 80 percent of pseudomonas strains. This is comparable, however, to many antibiotics.
-Second, and more limiting, is the development of resistance. Even when the appropriate bacteriophage is applied to the appropriate host, the host bacterium has the ability to mutate its receptor and enlist other defenses to evade the phage. This problem can ben circumvented by using multiple phages, identifying new phages or trying to mutate the original treating phage to recognize the changed host bacterium.
These two problems, along with the inherent advantage of the biofilm structure preventing absorption of the phage, makes phage therapy in human disease a little more challenging, but not impossible.
In phage therapy for chronic wounds several strategies have been pursued.
-First, debridement of the wound causes a significant disruption of the physical barriers to absorption and improves the kill rate of the phage.
-Second, combining phage therapy with antibiotics, such as macrolides (which disrupt the EPS material) or other antibiotics that challenge the environmental edge may make the biofilm more susceptible to phage penetration.
Also, multiple applications, or even continuous application, of phage may overcome some of the problems with absorption and, therefore, infection of the biofilm.
Phage products such as depolymerase, holins, and lysins are being developed and studied for their possible use in infectious diseases.
Also, more targeted research is being done on broader host range phages, developing cocktails with better phage synergies and more virulent phages.
