Phage therapy: Is it the best alternative approach against increasing antibiotic resistance in future?

Antibiotics- the class of drug has saved many million lives over the last several years. Antibiotics have been the first line of defense in mankind’s war against infection-be it a simple community acquired pneumonia or life threatening septicemia. But unfortunately we have just managed to win a few battle against infection-we have not won the war. Our opponents, the bacteria, always seem to be back in battlefield, stronger and resistant to our armory of antibiotics and thus gained “Antibiotic resistance”.

Antibiotic resistance is an emerging global health crisis, resulting from the continuous use and misuse of antibiotics in healthcare, farming industry, and elsewhere. Phage therapy refers to the utilization of bacteriophages (or just phages, viruses infecting bacteria) to treat bacterial diseases. Given the increasing number of drug-resistant bacterial infections, especially within hospital settings, the exploration of alternatives to conventional antibiotics has become an important research objective. Bacteriophages are very abundant and every bacterium is likely to have their own specific viruses that could be utilized as antibacterial agents means phages are very specific against particular bacterium.

Fig: Bacteriophage in action

Historically, phages were used therapeutically already in the early 20th century (in 1920s). But by 1940s due to the discovery of broadly effective antibiotics led to the demise of the development of phage therapy in western countries and only as the antibiotics are starting to fail there has been a serious attempt to restore the old tool. However, the second coming of phage therapy faces challenges regarding to the strict regulatory guidelines and the development of effective therapeutic practices. Yet, phage therapy can provide an evolutionarily sustainable alternative to  conventional antibiotics ,should we be able to adjust our regulations and procedures to meet the special requirements of phage based medicine.

 The cause for the stip decline of phage studies in 1940s were at least three-fold: insufficient understanding among researchers of basic phage biology; over exuberance, which led, along with ignorance, to carelessness; and the advent of antibiotics, an easier to handle as well as highly powerful category of antibiotics. 

Now its high time, to look for the alternatives like phage therapy to deal with the antibiotics resistance bacteria and do intensed research with an aim :

1. To provide an overview of the potential of phage therapy as a means of treating or preventing human diseases.

2. To explore the phage therapy state of the art as currently practiced by physicians in various pockets of phage therapy activity around the world, including in terms of potential commercialization;

3. To avert a recapitulation of phage therapy’s early decline by outlining good practices in phage therapy practice, experimentation, and ultimately, commercialization.

The protocols for bacteriophage isolation can vary depending on the sample type and the desired outcome. However here are some general steps that are commonly followed and they are:

  1. Sample collection: Collect the sample from the environment or host organism. The sample can be soil, water, feces, or any other biological material.
  2. Preparation of sample: The sample is filtered to remove debris and bacteria that are not susceptible to bacteriophages.
  3. Enrichment: The sample is enriched with a bacterial host that is susceptible to the bacteriophage of interest.
  4. Isolation: The bacteriophages are isolated from the enriched sample using various techniques such as plaque assay, double-layer agar, or filtration.
  5. Purification: The isolated bacteriophages are purified to remove any remaining bacterial debris or other contaminants.
  6. Characterization: The purified bacteriophages are characterized using various techniques such as electron microscopy, DNA sequencing, or host range analysis.

For more detailed information on bacteriophage isolation protocols, you can refer to the book Bacteriophages: Methods and Protocols, Volume 1: Isolation, Characterization, and Interactions 

Fig: Strategies of phage therapy

 Conventionally, phage therapy relies on the use of naturally-occurring phages to infect and lyse bacteria at the site of infection. Biotechnological advances have further expanded the repertoire of potential phage therapeutics to include novel strategies using bioengineered phages and purified phage lytic proteins.

Current research on the use of phages and their lytic proteins, specifically against multidrug-resistant bacterial infections, suggests phage therapy has the potential to be used as either an alternative or a supplement to antibiotic treatments.

Staphylococcus aureus (S. aureus) is the most virulent pathogen causing various diseases, including
skin abscesses, pneumonia, endocarditis, and osteomyelitis, in humans and animals. The two major sources of infection include community and hospital. The bacterial strains are resistant to many antibiotics, and especially to methicillin and vancomycin. The emergence and prevalence of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant S. aureus (VRSA) underscores the need for development of effective therapeutic alternatives.

Phages are the most common organisms on the planet and represent great diversity in host range. S. aureus phages target pathogens in diseases, such as bacteremia, eye infections, and S. aureus-associated lung infections. Compared with traditional antibiotics, bacteriophages are cost-effective without serious side effects, and are virulent especially against drug-resistant bacteria. Further, phages generally recognize specific receptors on bacterial cell membrane, without affecting human, or animal cells. Therefore, the side effects in eukaryotic hosts are minimal. Studies involving S. aureus phages show effective and comprehensive antimicrobial activity in vitro and in vivo.

The concept of a self-replicating, self-regulating natural antimicrobial that can penetrate into the most sequestered corners of the body and selectively combat pathogens is very exciting. Phage therapy clearly has many special advantages: the ability to target specific pathogens with minimal destruction of normal body flora, the ability to cross physiological barriers such as the blood-brain barrier and get into the furthest depths of osteomyelitis in a bone, the ability to disappear with little or no trace when the pathogen is no longer present – making phages logical partners of our natural bodily defenses and potential pillars when they break down. The field of phage therapy, including human phage therapy, has been making progress as novel phages, technologies, and techniques are introduced, along with a greater modern understanding of phage biology, phage ecology, and the roles of phages in maintaining microbial balance in general has

Further development of phage therapy as a common alternative to strictly chemical-based treatment of bacterial infections in humans, however, will require far greater and sustained investment than has so far been the case, particularly in basic research. While the need for this alternative to antibiotics is very pressing, it is important to evolve the basic scientific understanding along with the new regulatory frameworks that are necessary and important to avoid repeating the mistakes of the past, and to develop first the areas of phage therapy that are most proven to be effective, such as its use against MRSA and other forms of Staphylococcus, which have been recognized as successful targets since the 1930s.

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