How scientists are turning to Phages in the war against harmful bacteria
Some of the world’s smallest microorganisms are being marshalled into an army powerful enough to defeat one of humanity’s greatest foes: antimicrobial resistance.

Look at a Phage under a microscope and what you will see closely resembles one of aliens from HG Wells’ classic novel “The War of the Worlds.” There is a head, made up of DNA covered by a protein coat and tentacles, which inject the Phage’s DNA into its prey before replicating and then killing the host (bacteria).

Phages are a type of virus and they are extremely abundant (there are more on planet Earth than stars in the universe). They are also infinitesimally small. At about 24 to 28 nanometres in length, they are many hundreds of times thinner than a human hair.

Over the past few years, they have come under the spotlight as a potential new weapon to kill harmful bacteria. For the past 70 years, the world has relied on antibiotics to cure the kind of bacterial infections that regularly killed our ancestors.

However, overuse means that some bacteria have evolved and become resistant to antibiotics The most dangerous now have a term of their own, Eskape, after six particularly dangerous strains: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species.

As the UN stated in 2019: “Unless the world acts urgently, antimicrobial resistance will have a disastrous impact within a generation”.

The potential for Phages has been known for over a century. Yet, while Alexander Fleming rapidly became one of the world’s most famous scientists accidently discovered penicillin in 1929, the same did not happen with the man who first publicly used a Phage. That may now change.

In 1919, the French-Canadian microbiologist Felix d’Herelle successfully cured a 12-year old boy of dysentery using phage therapy. However, across most of the world, the treatment never flourished as antibiotic use grew instead.

This is because there are a number of hurdles to overcome before Phages can be truly commercialised. Firstly, it takes time to identify the bacteria causing the problem and this is far more time-intensive and costly than simply prescribing a pill. Secondly, Phages and bacteria are in a constant evolutionary “arms race” with each other: one seeking to kill, the other to survive.

However, when the correct match is made, Phages can be as effective as a sniper, killing the dangerous bacteria without harming the beneficial bacteria that live inside us.

Antibiotics have the opposite effect. They are fast acting, but take a scattergun approach, killing both the harmful and beneficial bacteria. They are also not as effective against certain types of medical conditions such as bone and joint infections because it is far harder for the drugs to penetrate through bone.

At Medix, we have recently had a couple of extremely complex cases involving these kinds of life-threatening infections. In both cases, the patients responded well to Phage treatment.

It is still early days. As yet, there are only a handful of centres across the world that have the relevant expertise. A number are located in former Soviet Union states, which had less access to the antibiotics developed by Western countries during the Cold War decades after World War 2.

Scientists are now trialling a number of different techniques to make phage treatment more effective. These include: phagograms to speed the identification process; phage cocktails, which seek to stack the odds by introducing multiple Phages at once and; gene editing to help the Phages stay one-step ahead of mutating bacteria.

Phages and antiobiotics can be used in tandem to increase the overall chances of success. For example, Phages can help to break down the biofilm, which bacteria produce to protect themselves, enabling the antibiotics to get through.

Over the past couple of years, a number of biotechs have launched clinical trials and the medical world is hopeful that the first truly widespread treatments will arrive within the next decade. Here are some of them:

Phico Therapeutics: the UK company has been conducting pre-clinical trials for an antibacterial technology called SASPject, which targets pseudomonas aeruginosa. The Phages are genetically modified with a special gene. This is injected into the bacteria, encoding it to produce a small acid-soluble spore protein (SASP), which disables the bacteria before it has time to mutate.

Queen Astrid Military Hospital: The Belgian hospital hit the headlines earlier this year when it used phage therapy on a woman injured during the 2016 terrorist attack in Brussels. She had developed a fracture-related infection that was no longer responding to antibiotics. Doctors got in touch with Georgia’s Eliava Institute, which was able to match her bacteria with a Phage from their own library bank. Researchers increased the Phage’s chances of success by growing it alongside the bacteria, continually taking the virus that killed the most bacteria and using that to create a new generation of virus that could outcompete the mutating bacteria.

BiomX: The Israeli biotech has already concluded Phase 1 clinical trials studying two cocktails, each with five Phages against Klebsiella pneumoniae, which is prevalent in a number of digestive disorders including IBD (inflammatory bowel disease), Crohns and ulcerative colitis.

Pherecydes Pharma: The French biotech is conducting phase I/II clinical trials for a surgical procedure called PhagoDAIR (debridement, antiobiotics, implant, retention). This is targeting Staphylococcus aureus infections in knee or hip joints.


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