Phage therapies vs. Antibiotics ¿There is a clear victor?

If you don’t know multiresistant bacteria (MRB), you should. These bacteria are responsible of the death of 700.000 people over a year, and it has been estimated it will be 10 million by the end of 2050 year If we don’t find a treatment to stop them. MRD appeared because they have developed resistance against antibiotics, mainly because of the bad habit we have on them, and they are extremely dangerous. Luckily, virus could help us to beat them. Specifically, the ones called bacteriophages. I join you to find out how.

 

There is an alert to the emergence of multiresistant bacteria. The WHO has published a list of those for which an immediate antibiotic is required. In view of not having it in a short term, what other option do we suggest?

 

Pseudomonas, Staphylococcus aerus, Escherichia coli, Enterococcus faecium, Streptococcus pneumoniae, Aeromonas hidrofila, Mycobacterium tuberculosis, among other, are the names of the bacteria which are being found multiresistant population that mock the action of antibiotics. We have in our hands the possibility of beat them, giving our trust to the use of bacteriophages, coming out the Phage Therapy.

Phage Therapy emerges as a substitution of antibiotics, when they aren’t effective against bacterial infection. This treatment consists in the use of bacteriophages (phage) as bactericide. It’s a virus that recognise, infects and destroy bacteria cells through a lytic cycle. This phages have a high specificity: they can infect one or a few strains of a bacterial species, so they are not only harmless against eukaryotic cells but also for our microbiota, so Phage Therapy would not harm the treated person. Many times, antibiotics can’t be given to immunosuppressed people because of the risk involved.

 

Electronic micrograph of bacteriophages, the viruses that Phage Therapy would use, adhering and infecting a bacterium. Source: wikipedia.

 

How Phage Therapy acts?

When the phage is supplied, it establishes a highly specific recognition against certain receptors on the surface of the bacterium, with which it interacts and adheres to its surface. After this, the phage enters its genetic material inside the bacteria. In the lytic cycle, the phage takes advantage of the bacteria own resources to produce the synthesis of mRNA necessary to generate copies of the capsid, viral nucleic acids and viral enzymes that will help to lyse the bacteria and kill it. So that, from a single phage, hundreds of them are generated inside the bacteria, which leave the host once their components are assembled, destroying it.

 

Lytic cycle of a bacteriophage against an enterobacteria. Source: Flirck, Credits: Saraesunbuennombre, CC: Attribution-NonCommercial-ShareAlike 2.0 Generic (CC BY-NC-SA 2.0)

 

These hundreds of newly synthesized phages constitute a new antibacterial dose, which presents a great advantage as it is possible to treat the patient with a single dose of phage. In addition, phages can reach sites that antibiotics cannot, and can be used as a preventive treatment.

Another advantage of phages is that their production is much faster than antibiotics, since it is much easier to select new phages than to find a new antibiotic.

Despite the advantages, there are also problems in Phage Therapy, which delay their commercial use. Among them we find the following, many of which we will see that have been found a solution:

Some bacteria develop phage resistance through various systems. The main one consists in the mutation of the receptors that phages use as a recognition element. To solve this problem, it is counterattacked with a cocktail of phages with different mechanisms of infection, which ensure that, although the bacterium generates resistance to infection, it does not do so against all phages.

The next problem is at the regulatory level. Most of the time the US FDA rejects Phage Therapies based on the use of phage cocktails. There is also difficulty registering them as intellectual property. However, there is a political interest at European level for using phagetherapy, for reasons included in the European Parliament’s Motion for a Resolution on the promotion of Phage Therapy.

Another difficulty lies in the release of endotoxins by certain bacteria when they are lysed which can harm the patient. To solve it, Anakiraman Ramachandran, president of the Canadian biotechnology company GangaGen, proposes to use genetically modified phages. The modification consists on the elimination of the gene responsible for producing endolysins, hydrolytic enzymes responsible for the destruction of the bacterial membrane that allows the release of the new phages. The hundreds of new phages are assembled inside the bacteria that ends up dying, without breaking, until finally it is phagocytosed.

Finally, two other cons towards Phage Therapy are the difficulties that exist in the delivery of the phages on demand and the formation of solid pharmaceuticals that produce them, as well as the negative perception associated with the use of viruses as a treatment.

Is there any production of phages at international level?

Yes, there is. The funny thing is that Phage Therapy were discovered long ago, so it’s not something new, but the West reject them by that time because antibiotics were found and chosen over Phage Therapy. Right now, things are different. In fact, regions as Russia, Georgia or Polonia have been many years using bacteriophages against bacterial infection, successfully.

 

Phage therapy was discovered many years ago, but the West rejected them in view of the appearance of antibiotics, delaying the research of Phage Therapies in the West. It may seem ironic that, many years later, now we are ready to bring that idea back, an idea that has been working and applied as a treatment for years in Russia, Georgia and Poland. Source: pixabay.

 

In Georgia we found Tbilisi Centre. In Polonia we also find the HirszFeld Institute, responsible for providing treatment to more than 5500 bacterial suppurative infection cases, in which the 90% of the patients were recovered with succeed.

Nowadays, more industries are beginning to investigate the therapeutic use of bacteriophages, including: Intralytix (Baltimore, USA), New Horizons Diagnostics Corporation (Columbia, USA), Exponential Biotherapies (Washington, USA), Novolytics (Coventry, UK), Phage-biotech (Revobot, Israel), Eliava Institute (Georgia), Phage Therapy Center (Tbilisi, Georgia), Special Phage Services (Brookvale, Australia), Gangagen (Ontario, Canada), Biopharm Pharmaceuticals (Tbilisi, Georgia) , Biophage Pharma Inc (Montreal, Canada) and Biochimpharm (Tbilisi, Georgia).

 

Thanks to these companies, today there are commercialized products that use bacteriophages. However, all of them are intended for sanitary control of the food, environmental control and vet, but none for treatment against bacterial infections on humans, although it has been resorted to as an experimental therapy in some countries, such as Poland. This is because there’s still some obstacles that we need to solve: we must find a drug that contains an adequate concentration of phages and that these can remain stable in it. Interestingly, among the treatments in development that we can find against bacterial infections in humans, most of them are not usually constituted only with bacteriophages, but usually come combined with other components, among them, antibiotics. Therefore…

 

“…antibacterial Phage Therapy, far from becoming a competitor to industries that market with antibiotics, can also become a strong ally. Unity makes strength.” 

 

Bacterial infections in humans don’t have to be treated by choosing whether to use bacteriophages or antibiotics, but we can develop drugs that contain both components, betting on the best of each of them and finalizing a powerful treatment. Unity makes strength. Source: pixabay.

 

Among the different products in development, we can find PhagoBioDermTM.This drug is already developed by PolymerPharma and consists of an antimicrobial wound dressing/healing biodegradable polymeric film that contains bacteriophages (a set called Pyophage) and other components, among which we find antibiotics (ciprofloxacin hydrochloride), enzymes (chymotrypsin) and others (benzocaine, an anesthetic). The idea on which this drug is based consists of three main interactions:

  • Ciprofloxacin hydrochloride inhibits enzyme of bacterium DNA Gyrase, disturbing in that way the replication of DNA and synthesis of bacterial cell proteins. Ciprofloxacin affects microorganisms in both the propagation and recovery phase.
  • At the same time, Pyobacteriophage causes the lysis of 5 main pyogenic microorganisms, bacteria that cause an inflammatory reaction that includes the production of pus (Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, Streptococcus pyogenes, Proteus vulgaris, Proteus mirabilis), reveals immunopotentiating activity.
  • Finally, Chymotrypsin has proteolytic activity, destroys necrotic tissues and fibrotic formations like thrombus and blood clots, coagulates viscous exudates, helps the biodegradation of polymeric matrix.

Biodegradable polymer is a biocompatible matter that metabolizes in organism into amino acids, reveals innate bactericidal activity, accelerates the regeneration of injured tissues and epithelization, suppresses pro-inflammatory and stimulates anti-inflammatory factors. We can find how he acts here.

PhagoBioDerm. Source: PolymerPharm.

 

Undoubtedly, Phage Therapy has multiple applications and has many advantages over the use of antibiotics. The cons that we can find are not deterministic and can be overcome with time and the development of new solutions. There are opportunities for those who are willing to make solid pharmaceutical forms of phages, with different marketing designs. In addition, this field of research is still active and is developing other alternatives such as the use of enzybiotics, the lytic enzymes that produce phages (such as endolysins) to lyse bacteria.

Phage Therapy is not intended to completely replace the use of antibiotics, they can even be used in the same treatment.

 

Triumph of bateriophages and antibiotics against resistant bacteria.  Source: Inspira Biotech, Credits: David Valero Torresano.

 

And what about you, do you think phagetherapy is a good alternative to antibiotics?

 

Are Phage Therapies our best ally against multiresistant bacteria? Source: pixabay.

 

References:

Segundo A., N. y Hernández B., E. y López V., O. y Torres A., O. (2010). Los bacteriófagos como una alternativa en el tratamiento de enfermedades infecciosas Bacterianas (Fagoterapia). Revista Mexicana de Ciencias Farmacéuticas, [en linea] 41(3), pp.17-26. Available in: http://www.redalyc.org/articulo.oa?id=57916078003

Amparo Sanchez Hernandez

Contact by: equipoinspira@inspirabiotech.com

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