Phage Therapy: The Solution to Superbug Domination
We’ve all been there — the scratchy throat, the loss of voice, the relentless cough, and the unwelcome fever that disturbs our day and ruins our focus; a raging battle within our bodies. When illness strikes, we run to our doctors in search of our trusty allies: antibiotics. We expect the medicine to rush into our systems and vanquish the bacteria within. But what if I told you that the very weapons we have depended on for close to a century are now facing an unprecedented challenge and a new hope is emerging to combat antibiotic resistance?
In this article, I will explain and explore the use of bacteriophages to combat antibiotic resistance.
Antibiotics
Antibiotics are one of mankind’s greatest discoveries. Over 100 antibiotics exist to treat different bacterial infections, from life-threatening ones such as pneumonia and sepsis to minor ones like conjunctivitis (pink eye) and otitis media (ear infection). This treatment can be created synthetically with chemicals or derived from molds.
Antibiotics primarily function by inducing cell death (bactericidal). This is done by inhibiting the cell’s growth or reproduction by preventing DNA synthesis, RNA synthesis, cell wall synthesis, or protein synthesis.
The Return to the Pre-Antibiotic Age?
Now that we know why antibiotics are amazing, imagine the damage it would cause if they stopped working.
Not so amazing.
“It is not the most intellectual of the species that survives; it is not the strongest that survives; but the species that survives is the one that is able best to adapt and adjust to the changing environment in which it finds itself.” — Charles Darwin
As Charles Darwin puts it, the “Survival of the Fittest” is truly a test of adaptivity. It applies to humans, animals, and plants so why should it not apply to bacteria?
Humans have been prescribing antibiotics for even the most minor infections for decades without knowing the true cause of the illness. While it has saved many, bacteria have learned to adapt. The overprescription of antibiotics as well as its use in farming has led to the evolution of bacteria.
Similarly to other organisms, bacteria are subject to random mutations or changes in their genome that can affect them in a positive, negative, or neutral way. When one bacterium is subject to a mutation that benefits its survival against a certain antibiotic, it thrives. Meanwhile, the bacteria that fail to adapt and resist the antibiotics are killed off in antibiotic-rich environments such as hospitals. The resistant bacteria pass along the mutated gene through different methods: reproduction, conjugation, and release of DNA upon death.
In the same way that Darwin describes it, the resistant bacteria proliferate and the non-resistant bacteria are destroyed. This process of natural selection among different types of bacteria is what causes the takeover of superbugs.
Many strains of superbugs such as Acinetobacter baumanii and Pseudomonas aeruginosa are resistant to multiple types of antibiotics including beta-lactams.
It is predicted that by 2050, deaths related to multidrug-resistant (MDR) bacterial infections could outnumber cancer-related mortality.
Read that again.
The Solution: Bacteriophages
Bacteriophages (quite literally meaning “bacteria eater”) are viruses that only infect bacterial cells, not human cells. This is important. They are the most abundant biological agent on earth and were discovered in 1915 and 1917 by Frederick W. Twort and Félix d’Hérelle, respectively. This is not a new course of treatment– it was simply cast aside following the discovery of antibiotics.
There are many forms that a phage can take on such as an icosahedral phage (corticovirus), head-tail phage (T7), or a filamentous phage (Inovirus). They exist almost everywhere, the soil, the oceans, the sewage, etc.
So what makes these viruses special?
They are known for their bactericidal ability. Remember how antibiotics rely on this same concept? Well, phages are also capable of inducing bacterial cell death while leaving other cells alone. Similarly to other viruses, bacteriophages are very specific and generally only infect one species of bacteria. The process of binding specific receptors is necessary for reproduction and ultimately survival.
When a phage lands on a host bacterium, it can do one of two things:
- Lytic replication cycle (bactericidal): The phage releases its genome into the bacterial cytoplasm of the host. The enzymes coded by its genome shut down various processes that allow the functioning of the bacterium such as protein, RNA, and DNA syntheses. Using the host’s machinery, the phage replicates its enzymes and structural components. These parts then come together to form more copies of the original phage. The phages’ lytic proteins become active and hydrolyze the peptidoglycan cell wall and cause osmotic lysis due to the inflow of water. This process releases the phages in an explosion of the cell. This is the destruction of the bacteria due to infection by the reproduction of bacteriophages.
I like to think of the lytic replication cycle as a smartphone overheating. Imagine a user unlocking the phone and opening various apps simultaneously, this is the phage’s landing and infection. As the user continues, they open over 20 apps, turn on the camera, max out the speaker volume, and more. This represents the phage’s takeover of the machinery. The smartphone starts overheating due to this excessive activity. Let’s then envision that it has reached its capacity and ultimately shuts down: bacterial death.
- Lysogenic cycle (bacteriostatic): The phage releases its genetic material into the bacterial chromosome. The bacteriophage is now called a prophage because the DNA is integrated with the host bacterium’s DNA. During cell division of this bacterium, the chromosome containing both the bacterial DNA and the prophage will continue to be passed down making many cells. In the right conditions, the prophage can reactivate the lytic cycle and destroy the cell.
Continuing the phone analogy, this can be compared to hidden malware. At first, the bacteriophage infiltrates the bacterial cell, integrating its genetic material without immediate harm, just like malware quietly installing itself on a smartphone. Both remain concealed, coexisting with their hosts until an activating event awakens them. Just as an action on the smartphone activates hidden malware, the trigger event revives the bacteriophage, leading to disruptions within the host cell. Ultimately, the host cell’s fate mirrors the damage caused by the activated malware on a smartphone.
Phage Therapy — One Approach
Using this knowledge of how bacteriophages reproduce and infect specific bacteria, the notion of phage therapy was developed. This treatment is the administration of lytic phages (sometimes with the support of antibiotics) into a patient infected by MDR bacteria.
Phage therapy could be the answer to replacing antibiotics. Because of their shared bactericidal ability, both courses of treatment should in theory work.
And it has.
Dr. Tom Patterson, an HIV researcher at UCSD, was on vacation with his wife in Egypt when he was infected by one of these MDR bacteria. The culprit was the superbug Acinetobacter baumannii. The Pattersons’ story is a heartfelt one as Tom’s wife fought to save his life, using any means possible. He was treated intravenously with an injection containing a cocktail of phages targeted at his infection.
Tom made a full recovery.
“Viruses can be medicine” — Steffanie Strathdee (Tom’s wife)
Conclusion
So, is phage therapy the solution to combating this global health crisis? Maybe it is, maybe it isn’t. Every day, scientists are making leaps in the search to find a solution to the global crisis that is antibiotic resistance.
Read about phage-mediated gene editing in my next article!
Stay tuned for more.
