Engage the phage: A solution to antibiotic resistance?

They’ve given us restriction enzymes, CRISPR/ Cas9, and now they might just be our answer to antibiotic resistance.

Writer: Katie Dale
Editor: Altay Shaw
Artist: Kate Morling

In 2015, doctors found a football-sized cyst in the biliary duct of Tom Patterson, a holiday maker in Egypt who thought he was experiencing a routine bout of food poisoning. But it was far more serious than that. The cyst contained Acinetobacter baumannii, one of the deadliest species of bacteria in the world, due to its extensive resistance to known antibiotics. Tom’s infection was resistant to every drug the doctors tested. When it reached his bloodstream, he was put in a medically induced coma, with his family told to prepare for the worst.

As a last resort, Tom was treated with an experimental cocktail of bacteriophages (phages), viruses that specifically infect bacteria, custom-made by scientists to treat his infection. Phages work in similar ways to common human viruses, like HIV and COVID-19. They first interact with a receptor on the surface of the host cell, and once inside they release their genetic material. They then hijack the cellular machinery, using it to make new virus particles. When the host cell can no longer cope, it bursts open, releasing the viral progeny and dying in the process.

Brutal for the bacteria, but the treatment saved Tom’s life. Three days after he was given the phage treatment, he awoke from his coma, and the long road to recovery began.

Phages are able to kill antibiotic-resistant bacteria because their mechanism of toxicity is completely different. Antibiotics are small molecule drugs that work by disrupting pathways critical to the survival of bacteria, for example the β-lactam antibiotic penicillin disrupts cell wall synthesis. Bacteria have evolved to evade these effects by producing an enzyme (β-lactamase) that breaks down the drug, actively pumping the drug out of their cytoplasm, or using other less common mechanisms. Antibiotic resistance has developed rapidly because we use tonnes of these drugs in agriculture, to keep our livestock healthy, and in medicine, to keep ourselves healthy, so we have created a strong selection pressure for resistant bacteria. On top of this, bacteria are able to rapidly share resistance genes through horizontal gene transfer, a process where DNA is passed from one bacterium to another.

We have reached a turning point in the past few decades where the pipeline of new antibiotics has dried up, and the number of drug-resistant infections like Tom’s is increasing. Just 15 new antibiotics have been put into clinical use in the 21st century, compared to 42 in the 1980s. It’s crucial that we find alternative strategies.

Phages offer a promising approach to solving the problem, as it’s much harder for bacteria to develop resistance to them. As the most abundant organism on Earth, there are thousands of different types of phage, each recognising a particular species of bacteria. This means that phages can be carefully selected to only kill the pathogenic bacteria causing illness, while leaving our friendly gut bacteria unaffected. It also means that there is likely to be a phage out there for just about any species of bacteria. However, identification of the right phage can be difficult, and isolation from its environmental source can also pose a challenge. Phages are enriched in dirty material such as sewage, requiring a lengthy purification process that is poorly suited to large-scale production. 

Researchers are currently developing libraries of characterised phages, as well as cocktails containing multiple types, as resistance can still occur. Bacteria have naturally evolved their own kind of immune system for defence against viral infection, including restriction enzymes and the CRISPR/ Cas9 system, which both function by cutting up the viral genetic material. They can also develop resistance to phages if a spontaneous mutation arises, modifying the receptor that the phage uses to recognise and enter the bacterial cell. This can work in our favour, however, as often it impairs the fitness of the bacterium. For example, one study found that treatment of the potato pathogen Eca with a flagellum-targeting phage caused the emergence of resistant variants with flagellum defects. This resulted in reduced virulence, as the bacteria were less motile and unable to spread to new uninfected areas of potato. 

In Tom’s case, when the Acinetobacter baumannii infection developed resistance, the fitness cost meant that the infection became sensitive once again to the antibiotic minocycline, which was then added to his treatment regimen. In the clinic, combining antibiotics with phage therapy has been highly successful, as they show a synergistic effect when used together.

So why isn’t phage therapy currently being implemented to fight antibiotic-resistant infections across the world? The best results are achieved with personalised cocktails containing different types of phage, but FDA regulations require each phage to go through clinical trials individually before a cocktail can be tested. This has limited pharmaceutical development, as production and testing of personalised therapies represents a substantial investment with little return. Although there have been clinical trials proving the safety of single-agent phage therapy, the future relies on trials that show safety and efficacy of phage cocktails. However, the results from case studies like Tom’s suggest we have an ace up our sleeves yet in the fight against antibiotic resistance, we just need to figure out how to play it.

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