The Rise of Phage Warriors: Revolutionizing Antibiotic Alternatives

Written by Alima Yahia

Deep beneath the radar, a silent war rages unseen. On one side lie the bacterial hordes, ancient enemies known for their plague and persistence, and on the other side, a weapon we’ve feared to wield — a viral assassin with a 99.99% kill rate.

This is the untold story of the virus bacteriophage — nature’s own secret weapon against the superbugs that threaten to plunge us back into a pre-antibiotic nightmare.

But wait, aren’t viruses the bad guys?

Not these ones.

Phages are the frontline warriors who fight in a microscopic battlefield, where viruses with razor-sharp precision infiltrate and obliterate their bacterial foes. While antibiotics spray bullets like a shotgun, phages are laser-guided missiles that target specific strains with accuracy. No collateral damage, no resistance build-up — just pure, brutal bacterial annihilation. This isn’t science fiction, it’s the future of medicine, and it hinges on unlocking the secrets of phages and understanding the weaknesses of antibiotics.

The Moldy Miracle that Went from Lab Bench to Battlefield

Admired for nearly a century, antibiotics have been and served as a vital remedy for many medical concerns ranging from sore throats and aching stomachs to fevers and coughs. The first discovery of antibiotics was in 1928 by Scottish physician and microbiologist, Alexander Fleming, who stumbled upon mold spores that produce what we now call Penicillin. After having difficulty in isolating the mold in large quantities, two scientists interested in penicillin, Howard Florey and Ernst Chain, were able to continue Fleming’s work and mass-produce penicillin for medical use during World War II.

Alexander Fleming discovered the mold that secretes Penicillin on the left. Penicillin being branded as a life-saving medicine through many cartoons on the right.

The Spectrum of Bacterial Relationships

In the vast and large world of bacteria, some bacteria are highly selective with whom they interact with while others cast a wider net. The social butterflies in bacteria are called ‘broad spectrum’ and kill or inhibit the growth of other types of bacteria. Pseudomonas aeruginosa is a broad-spectrum pathogen that produces a pyocyanin, a toxin, and elastase, which breaks down the host’s tissues and equips the bacteria to thrive in taxing environments. The picky, not-so-extroverted bacteria, on the other hand, are called ‘narrow-spectrum’ and target specific niches within the microbial community. Bacterial relationships can span from mutualism, where both species benefit and flourish, to commensalism, where one bacteria leverages the host’s resources without causing detriment.

Two Roads Antibiotics Take To Overthrow Bacterial Foes

In these two types of bacteria, there are two categories of antibiotics; they are either bacteriostatic or bactericidal.

Bacteriostatic agents do not directly kill bacteria but rather hinder their ability to reproduce and thus spread. These antibiotics interfere with DNA replication preventing the bacteria from spreading to other regions or with protein production decreasing the bacteria’s chances of survival. Ultimately, bacteriostatic antibiotics reduce the threat of harmful bacteria over time.

Bactericidal agents, on the other hand, employ strategies to kill the bacteria directly. These antibiotics inhibit cell wall synthesis by disrupting its construction which is a crucial element for molecular integrity and basic survival. A deficient or incomplete cell wall can lead to bursting and cell death. Other forms involve inhibiting protein synthesis which targets the ribosomes that are the protein-making machinery of the bacteria. By hampering the translation of DNA into proteins, these agents crash the cellular processes and starve the bacteria to death. Lastly, a bactericidal agent can also directly attack the bacterial DNA to precipitate lethal mutations and thus compromise the overall survival of the bacterium.

Fueling the Resistance

Although antibiotics work in numerous ways to kill harmful bacteria, resistance is spreading in a plethora of ways. For starters, pharmaceutical companies constantly advertise the uses of antibiotics in the market and prescribe them too freely to the general public. Furthermore, according to the US Centers for Disease Control and Prevention (CDC), at least 50% of antibiotics are prescribed in outpatient settings for health conditions not caused by bacteria. Improper antibiotic use accelerates the evolutionary arms race between humans and bacteria, creating resistant strains and superbugs.

Another outlet for the build-up of antibiotic resistance is in meat production. In June 2023, the United States Department of Agriculture (USDA) estimated that there are 9.6 billion birds for meat and eggs, 70.3 million hogs and pigs, and 91.9 million head of cattle and calves on U.S. farms. These animals held as livestock live in tight unhygienic conditions to make meat cheaper and also make for the perfect breeding place for diseases. To kill off bacteria and maintain their health, animals are fed antibiotics to evade sickness and sustain business gains. Unsurprisingly, as a result of this system, we recycle the resistance in humans when we consume the animals that build it first.

To tackle these superbugs, scientists also have super antibiotics that act as a last-line agent. However, in 2015, China reported the super antibiotic Colistin is no longer effective in destroying harmful bacteria. In other words, superbugs have built resistance against our last line of defense. This puts humanity in an unwanted situation as the bacteria’s resistance makes infections deadly again.

Another case study of superbugs was when a 70-year-old patient was diagnosed with an infection caused by carbapenem-resistant Enterobacteriaceae (CRE), a Gram-negative bacteria that is responsible for a wide range of infections including pneumonia and urinary tract infections. As a result of this antibiotic resistance, the patient’s health rapidly deteriorated resulting in death.

In 2019, the World Health Organization (WHO) estimated that there would be 700,000 global deaths as a result of antibiotic resistance and projected that number to increase to 10 million by 2050 if no action is taken. Common bacterial infections that have been treatable for nearly a century now will be potentially life-threatening again. Antibiotics are a failing solution solemnly leaving humanity’s forgotten and potentially last hope — bacteriophages.

A Weapon Bacteria Can’t Outrun

The ubiquitous bacteriophage, or phage, offers a superior alternative to antibiotics because they can zero in on specific bacteria strands with 100% accuracy.

Unlike antibiotics which often disable both good and bad bacteria like a bomb blast, phages are equipped with the ability to tailor their attacks because of receptors. Phages rely on specialized proteins called receptors on a bacteria and recognize its’ ‘match’ on the surface of their target bacteria, like a key fitting into a specific lock. Human cells lack these receptors, making phages harmless to us. Leaving the good bacteria alone is crucial for maintaining our overall health and digestion — it’s like taking out the weeds in a garden without harming the flowers.

Furthermore, since bacteria develop resistance to antibiotics quickly, phages naturally co-evolve with their targets without external involvement to survive too. They constantly adapt to stay one step ahead making them a more sustainable solution in the long run, unlike antibiotics, which bacteria can quickly render ineffective.

Learning and Deconstructing the Phage

Phages are everywhere — existing in the water and soil, inside our gut and saliva, and even in the coral reefs and oceans. To study phages, a sample is collected from the desired environment and a bacterial strain is introduced in the sample to emanate the phages. After some time is allotted for the phage to infect the bacterial cells, the phages are harvested through centrifugation, spinning down the sample and isolating the phages from the bacterial cells. Other methods involve adding a substance called polyethylene glycol (PEG) that bridges phages together on an atomic level or using filters with a pore size small enough to thwart bacteria and allow phages to pass through.

Moreover, because phages interact on a nanolevel, they are observed using a powerful imaging technique called electron microscopy that uses a beam of electrons, instead of light, to achieve higher levels of resolution, thus allowing for the magnification of the phages.

This is what phages look like under electron microscopy.

Phages are extremely diverse in size and shape and classified by the strand nature and DNA type of the phage. Its traditional structure is an icosahedron head with twenty plane faces and thirty edges that contain the genetic material of the phage that is protected by a protein called capsid. The head is connected to the tail, which acts as a pathway for the genetic material to pass into the host during invasion, and the leg-like fibers, which help ground the phage onto the host cell.

The Two Cycles of a Phage:

Once a phage finds a specific type of bacterium or one of its close relatives, it attaches to a susceptible host and pursues one of two cycles: the lytic cycle or the lysogenic/temperate cycle.

Lytic Cycle:

In the lytic cycle, a bacteriophage undergoes distinct phases: attachment, penetration, biosynthesis, maturation, and lysis. The process initiates as the phage attaches itself to the host’s surface. Subsequently, it penetrates the host by injecting its genome directly into its’ cell’s cytoplasm. Within the host cell, the phage utilizes its’ ribosomes to synthesize capsid proteins. This phase, known as biosynthesis, involves the rapid conversion of the host cell’s resources into the viral genome and capsid proteins, facilitating maturation. During maturation, multiple copies of the original phage are produced and the increasing assembly of phages exerts pressure on the bacterium, leading to the active lysis or bursting of the host cell. This rupture releases the newly formed bacteriophages, allowing them to repeat the entire process.

Lysogenic/Temperate Cycle:

The lysogenic cycle comprises different phases: viral attachment and penetration, integration, excision, infection, and recombination. Unlike the lytic cycle, the temperate cycle produces the foundations for phage multiplication without immediately bursting the host.

The initial phases involve viral attachment and DNA injection; however, after the phage DNA enters the bacterium, it refrains from immediate replication or protein expression. Instead, the phage DNA integrates with the bacterium’s chromosome, forming a prophage. Unlike the lytic cycle, the integrated prophage does not actively drive the creation of new phages. Instead, dormant genes coexist with the host’s DNA, facilitated by repressor proteins that regulate whether certain genes are turned ‘on’ or kept ‘off, and replicate each time the host undergoes asexual reproduction.

The phages encode repressor proteins that bind to specific DNA sequences on the host chromosome, preventing the switch to the lytic cycle. The prophage remains in a dormant state until exposure to factors like certain chemicals, radiation, or UV light activates it, allowing the subsequent progression of the lytic cycle to occur.

While both phage types ultimately lyse bacterial cells, strictly lytic phages are crucial for phage therapy because they act fast. They directly infect and burst the host cell, providing immediate relief from bacterial infections. In contrast, lysogenic phages may eventually lyse the cell, but this does little to immediately thwart bacterial infections.

From the Phage’s Hope to Skepticism

If phages could be used to directly kill bacteria, then why have we abandoned the idea of them entirely? Phage therapy actually predates the widespread use of antibiotics by only a few years. In 1915, Fedrick Twort, a bacteriologist from England, was the first to suggest that a virus could be used to kill bacteria. Two years later, Felix d’Herelle, a microbiologist at the Institut Pasteur in Paris, first proposed phages as a therapy for bacterial infections in humans.

Felix d’Herelle working in his laboratory with Phages

The first known therapeutic test and use of phages occurred in 1919 when d’Herelle and some hospital interns wanted to test the effectiveness of a phage. They first ingested a phage cocktail to survey its safety and then delivered it to a 12-year-old boy with severe dysentery, an infection in the intestines that causes bloody diarrhea. After a single dose, the patient’s illness cleared up and reached optimal recovery within a few days.

After this success, researchers continued to study and test phages for their ability to treat bacterial infections in humans in the 1920s and 30s. However, because the results were largely published in non-English journals, phage therapy research did not reach the US and Western Europe Therefore, it was largely suspected that the phages did not work all that well by the general public.

Furthermore, when a pharmaceutical company Eli Lilly launched in the 1930s/40s and produced phages for humans to use in the US, inconsistencies in product efficacy and broader societal shifts hindered the company’s marketing efforts. In such turbulent times, phage therapy fell out of the favor of the US and most of Europe and was replaced by the trusted, safe, and beloved — at the time — advent of antibiotics.

Phage Necessity Breeds Innovation

Although antibiotics were used during World War II, they did not reach some places such as the Soviet Union, including Russia, Poland, and Georgia. The Soviet Union was limited in many ways compared to Western countries such as their prioritization of military and industrial development, lack of robust pharmaceutical infrastructure, and latter disruptions from post-war.

However, regular institutions in these countries such as the Gamaleya Institute in Moscow, nationalized in 1923, and Eliava Institute in Tbilisi, founded in 1923, surprisingly conducted extensive research on isolating and characterizing phages. Early clinical trials led to successful reports that encouraged its use during World War II. Thus, phages were extensively employed to treat wounded soldiers suffering from bacterial infections.

Being that antibiotics are more widespread today, Russia, Georgia, and Poland currently use these drugs as their mainstream medicine but still allocate time for researching phages. Russia has some registered medicines and participates in clinical trials, Georgia is currently working on characterizing and isolating phages, and Poland is working on therapeutic and clinical trials.

Phages Used Outside of Laboratories

With the growing threat of antibiotic-resistant bacterial strains that are killing more lives than cancer, there has been an increased interest in phage therapy as an alternative. In the 1980s, Western scientists ‘re-discovered’ phage therapy and began human experiments again in the 2000s.

Published in 2009, a pioneering phase I clinical trial assessed the safety of a multi-phage cocktail targeting E. coli, Staphylococcus aureus, and Pseudomonas aeruginosa in 42 patients suffering from chronic, non-healing leg ulcers. This study administered the phage cocktail weekly for twelve weeks and monitored the patients for an additional twelve weeks. While only focused on safety, the trial demonstrated no adverse effects from the phage therapy, offering valuable insights for further research into its potential effectiveness in treating chronic wounds.

A most famous case of phage therapy usage was the 2016 case of a researcher at UC San Diego Health, Tom Patterson. Patterson contracted a deadly infection called Acinetobacter baumannii while on vacation in Egypt and could not control the infection through available forms of antibiotics. His wife, Dr. Setffanie Stratdee, now Co-Founder and Co-Director of the Center for Innovative Phage Application and Therapeutics, tried to find anything that could save Patterson and eventually came across bacteriophages.

She scanned pre-existing phage libraries, isolated new phages from sewages and barnyard waste, and found a phage that could kill Patterson’s infection. After success, Patterson received an intravenous phage cocktail that immediately improved his health. Making a full recovery from his illness, Patterson’s high-profile case brought phage therapy into light, growing the number of case studies in the US and Western European countries.

Tom Patterson and his wife Steffanie Strathdee are helping combat antibiotic resistance by paving the way for Phage Therapy usage. Strathdee published a book called “The Perfect Predator: A Scientist’s Race to Save Her Husband from a Superbug” detailing her experience of using phage therapy to save her husband.

The Uncertain Consequences of Phage Therapy

When antibiotics are taken, the concentration decreases over time, while the number of phages increases via rapid multiplication when killing the bacteria. In other words, the dose of the phage cocktail that is administered to the patient is not the exact dose a patient would receive. Therefore, the self-replicating feature of phages influencing treatment efficacy and causing unfavorable health consequences is still unknown. Pharmacokinetic and pharmacodynamic studies about the drug’s journey and effects need to be done to understand what happens to a phage after it is delivered to a target area.

Another barrier is the slight chance that the bacteria build resistance to phages to survive. Although not impossible, the development of resistance actually wouldn’t be a bad thing. A bacteria developing resistance to phages can act synergistically with antibiotic use since the bacterium would have to forfeit its resistance to antibiotics to sustain itself from phages.

From Forgotten Remedy to Last Hope: The Rising Tide of Phage Interest

Despite the varying obstacles and previous suspicions, phage therapy usage is promising. Strathdee emphasized that the FDA is “on board” with phage therapy and there is increased dialogue between phage therapy developers and regulatory bodies such as the FDA and European Medicines Agency, which paves the way for a more streamlined process. In fact, the U.S. National Institute of Health (NIH) awarded $2.5 million to 12 global institutions to study phage therapy. Further, clinical trials are receiving more attention and show promising progress in combating adamant pathogens.

My Inspiration for looking into Phage Therapy

My fascination with Phage Therapy has deep roots in my personal journey. Whenever illness strikes, it’s inevitably strep from exposure to extreme temperatures, a result of being a daytime brux, inhaling dust, and getting stressed out. In my earlier years, my go-to remedy was Amoxicillin, until one day it led to a severe allergic reaction, manifesting as hives across my body for an entire week. It took the medical professionals two weeks to identify the cause — a reaction to an antibiotic that had been a lifesaver for me every month. Since then, I’ve oscillated between Clindamycin and Azithromycin.

Just recently, however, when a bout of strep led me to take Azithromycin, it resulted in significant side effects like lower abdominal pain, nausea, and dizziness. It was during this time that I stumbled upon Phage Therapy on TKS.life, and it immediately struck me as a transformative solution that both I and the world needed. It offers a way to circumvent potential resistance, eliminate unwanted side effects, and avert the adverse consequences of bacterial resistance.

Bacteria mutate, humans research, and problems are solved. Our knowledge and approach to phage therapy is evolving every day so the fight against antibiotic-resistant bacteria is far from over. I am driven by a profound desire to revolutionize healthcare and streamline Phage Therapy into regular medicines, ensuring a safer and more effective approach to combatting bacterial infections. Phage Therapy is the longed-for answer humanity is looking for, a medical revolution the world requires, and a war we will most certainly win knowing the secret of

Don’t Click Away!

If you’re interested in my work, have any related questions, or would love to sit down and have a chat, don’t hesitate to reach out to me on LinkedIn!

https://www.linkedin.com/in/alima-yahia-0a0755279/

Article published with the permission of Alima Yahia

https://medium.com/@alimayahia01

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