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Bacteriophages as a Diagnostic and Therapeutic

Global Health Surveillance Human Health

Capitalizing on Nature’s Antibiotic  

Bacteriophages (phages) are everywhere, the most numerous viruses in the world. They colonize your hands, the inside of your mouth, lungs, and even your gut. Without so much as sneeze or a cough, you’re transmitting them to everyone around you. And they are the deadliest viruses on the planet … but only to bacteria.  

A simple structure, phages consist of their genetic material, either DNA or RNA, which is encased in a protein coat. They then have a tail and tail fibers. It is the latter that helps the virus transit across a susceptible bacterium and attach itself to infect the host cell.  

There are two types of phages:  

  1. Lysogenic, in which the phage replicates within the bacteria and the viral genes are passed on to daughter cells during cell division without destroying the bacterial cell. 
  2. Lytic, in which the phage attaches to the bacterial cell through a viral protein on the phage surface to receptors on the bacterial cell surface. The phage then will inject its genetic material into the bacteria, commandeering the bacteria’s protein and nucleic acid synthesis machinery to replicate its phage components. Once it does, it replicates itself and creates new viral particles until causing the cell to lyse, breaking apart the cell and releasing the phage’s viral progeny into the environment, continuing that cycle. 

Benefits of Phages as a Diagnostic 
By engineering phages to be a reporter, they can be used as a very simple and cost-effective diagnostic, identifying specific bacteria to the species or even strain level. Additionally, phages are self-replicating, which allows for signal amplification with very minimal preparation or work on a technical level.  

Phages are unique in that they only detect viable cells. That’s a key difference between phage detection and methods like PCR, which will detect any DNA or RNA related to the bacteria in question, whether it was live bacteria or not. They also have a rapid readout that is often between 1-4 hours, though there are some studies that manage to get a readout between 10-30 minutes, which is quite fast for a diagnostic. 

Several studies have also assessed that they have a very long shelf life and the ability to be freeze-dried into a powdered form, which could be useful in a field-forward or remote setting. Read more in “Field-Forward Devices Democratize Diagnostics.”  

Phage Display Technology
In certain contexts, phages can also be used as diagnostic tools for human diseases. The use of phage display technology involves expressing foreign peptides or proteins on the surface of phages. These displayed peptides or proteins can then be used to bind specific targets for diagnostic purposes. 

Displaying antigens or epitopes on phages can be used to detect the presence of specific antibodies and patient serum samples obtained from blood. In the past 10 years, technology has been developed to use phages engineered to act as biosensors by displaying a protein that gives off a signal which specifically binds to a target molecule. These phage-based biosensors can be used for rapid and highly specific detection of disease markers or pathogens, which could enhance the accuracy and speed of diagnosis, leading to an improved clinical outcome. Research shows that diagnostic assays using this technology can even outperform conventional culture-based and molecular detection methods. 

Benefits of Phages as a Therapeutic
Phages have been explored in veterinary medicine as an option to treat bacterial infections in livestock, house pets, and aquaculture. In these cases, the virus infects and replicates within bacterium, leading to their destruction. This makes phages potential candidates for targeted antibacterial therapy and an alternative or complementary treatment to antibiotics. 

While bacteriophage therapy holds potential, there are challenges and considerations. It is important to use phages that specifically target and kill pathogenic bacteria without affecting beneficial bacteria or causing resistance issues. Just as with antibiotics, misuse could prompt phage resistance, leading to stronger bacteria. While this may not necessarily eliminate their therapeutic efficacy, it may lower it. 

This is why phage cocktails are recommended. If using only one phage and there is at least one bacterium with resistance, it can then proliferate and the new bacterial population growing from that cell will all have resistance. Using multiple phages increases the chances of elimination of the bacterial population. Even if there are a small number of bacteria resistant to one of the phages used, another phage in the cocktail will kill it.  

The role of phages as potential therapeutics for animal health only scratches the surface, as these applications could readily translate to human health.  

Phages as an Alternative or Supplement to Antibiotics
Another option is to combine the usage of phages with antibiotics. Research has shown that when a bacterium develops resistance to a phage, it tends to shed its resistance to antibiotics.  

Too, while antibiotics are a chemical that is isolated from a natural source—like penicillin was originally isolated from a fungusthey don’t evolve over time. Phages are different in that they have been evolving along with bacteria for billions of years just to survive, as they can only replicate in a bacterial host cell. Because of this, when developing therapeutics with resistance in mind, phages offer a compelling alternative or supplement to antibiotics.  

Research and clinical trials have investigated phages as therapy for various bacterial infections, including those caused by antibiotic resistant bacteria, wound infections, respiratory infections, urinary tract infections, and others. Similar caveats to those animal therapeutics exist, including the need for specificity of the phages. As with any potential human therapeutic, nonclinical and clinical trial testing for safety and efficacy must be evaluated. 


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