If you have a list of things that bacteria fear, the phage is above. These viruses are built to find, infect and kill them, and have been doing it for billions of years. Now, ancient battles provide clues on how to fight back against antibiotic-resistant infections.
As more bacteria evolve to withstand our antibiotics, previously treatable infections have become more difficult and sometimes impossible to treat. Known as antibiotic resistance (AMR), the crisis has already caused more than 1 million deaths worldwide per year, and its numbers are rising rapidly. The World Health Organization has named AMR one of the top 10 public health threats worldwide.
Phage therapy – using phages to treat bacterial infections – has attracted attention as a potential solution. Phages are highly specific and can even target drug-resistant strains. In some compassionate cases in the UK, they cleared all antibiotics failed infections. However, phages still face a challenge that is often overlooked: the bacteria themselves.
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Bacteria have evolved sophisticated systems to detect and destroy phages. These defenses are diverse. Some cut out viral DNA, others block invasion, others activate a kind of intracellular shutdown to prevent virus acquisition. In a new study published in Cell, my colleagues and I describe a system that works in a different way called Kiwa. It acts like a sensor embedded in the bacterial membrane and detects early signs of attack.
While exactly what Kiwa is sensing remains an unresolved issue, our findings suggest that phages respond to the mechanical stress that occurs when they latch into a cell and inject its DNA. When triggered, the kiwa runs fast. It shuts down the phage’s ability to make the necessary components to build new phages and stops infection before taking over the cells.
But just as bacteria evolve the way they protect themselves, phages evolve the way they fight back. In our latest experiment, two strategies were played.
Related: “Drugs Needed a Substitute”: How “Phage Whispeller” aims to replace antibiotics with viruses
Some phages developed small mutations in the proteins used to attach to the bacterial surface. This is a subtle change that helps avoid triggering Kiwa’s detection system. Others took a different approach: they allowed themselves to detect, but they escaped the outcome.
These phages carried mutations into viral proteins that appear to be involved in the way Kiwa shuts down infections. I’m not sure exactly how this works yet, but the results are clear. Even after Kiwa is activated, the virus continues to replicate with just a few changes.
This evolutionary flexibility is part of what makes phage so powerful, and part of why they hold such a promise to treat infections. But it also highlights an important issue. To make phage therapy effective, we need to understand how these microorganisms fight unfold.
Engagement rules
If a bacterial strain carries a defense like the Kiwa, not all phages will succeed against it. Some may be blocked completely. But others may slip through just with the right mutation. In other words, choosing or engineering the right phage for your job is not just a matter of trial and error, it’s a matter of knowing the rules of engagement.
Researching bacterial defense systems like Kiwa will give you a deeper understanding of these rules. It helps explain why some phages fail, why others are successful, and how to design better phage therapy in the future. Eventually, one may be able to predict which bacterial defenses a particular strain will carry and choose naturally equipped or artificially tuned phages to overcome them.
That’s the idea behind the growing phage collection project. We collect phages from all over the UK, including public submissions – dirty water is often gold mines – and we test them to see which ones can overcome the defenses carried by dangerous bacteria. With over 600 types already catalogued, we have built resources that can guide future phage therapy, combining the right phage with the right infection.
Kiwa is just one puzzle. Bacteria encode many of these defensive systems, each adding a layer of complexity and opportunity to this microbial weapons race. Some people directly detect viral DNA, others sense damage and stress, while others regulate their response with adjacent cells. The more you learn, the more accurate you can intervene.
This is not a new war. Bacteria and phages have been trapped in it for billions of years. But for the first time I’m starting to listen. And if they learn how to navigate evolved strategies, they may find new ways to treat infectious diseases that antibiotics can no longer handle.
This edited article will be republished from the conversation under a Creative Commons license. Please read the original article.
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