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New insights could help phages defeat antibiotic resistant bacteria

Researchers at the University of Southampton have worked out how bacteria defend themselves against viruses called phages and the new insights could be key to tackling antibiotic resistance.

Phages are seen as a promising alternative treatment to antibiotics. Unpicking how bacteria protect themselves, and how phages might overcome these defenses, could be a significant step in defeating antibiotic-resistant bacteria.

Phages, known as bacteria eaters, look like a syringe with spider legs. They work by attaching themselves to bacteria. Once locked on, they inject their DNA into the bacterial cell, hijacking it to produce more copies of the virus before the cell bursts open and releases the new phages to attack other bacteria.

Crucially, phages only attack bacteria and are harmless to human cells.

The new research, in the journal Cell, is the first to describe how a bacterial defense mechanism against phages, called Kiwa, works. The paper is titled "Kiwa is a membrane-embedded defence supercomplex activated at phage attachment sites."

"In Māori mythology, Kiwa is a divine guardian of the ocean and its creatures," says Dr. Franklin Nobrega, Associate Professor at the University of Southampton and National Institute for Health and Care Research (NIHR) Southampton Biomedical Research Center (BRC) Unit.

"In bacteria, Kiwa also acts as a guardian, defending against phages, and are one of the most common defense mechanisms bacteria have."

Researchers used advanced imaging techniques to study the interaction between phages and Kiwa at a molecular level.

They found Kiwa is made up of two components called KwaA and KwaB. This duo works together to form a kind of chainmail around the bacteria, preventing the phage DNA from entering. KwaA acts like a sensor detecting the presence of a phage. Once this sensor is tripped, KwaB is alerted which binds to the phage DNA and turns it off before it can take over the cell.

But some phages have evolved a clever way to break through this two-step security system. They release a 'decoy' protein called Gam which tricks KwaB into attacking them while the real phage DNA slips through to complete the hijack.

Unfortunately for the phages, and us, Kiwa is one of many defense mechanisms bacteria have. Another is called RecBCD, which also detects and attacks phage DNA. While the decoys work well against both systems independently, when they combine, phages can't break through.

Dr. Nobrega explains, "In a similar way to how hackers are constantly looking for ways to bypass security systems, phages have evolved ways to breach the defenses of bacteria. But just as tech companies adapt by releasing their latest updates with improved security features, bacteria have evolved their own molecular firewalls in the shape of Kiwa and RecBCD."

Finding new ways to fight bacteria is a pressing concern due to the growing threat of antibiotic resistance, which could kill ten million people a year by 2050 and costs the NHS £180m every year.

Dr. Nobrega and his team at the University of Southampton are which have the potential to overcome bacterial defenses, and have identified over 600 different types to date.

They are inviting people (the perfect breeding ground for bacteria and phages) and post it into the lab for analysis.

"By improving our understanding of how these defense mechanisms operate, we can work out how to exploit weaknesses and select phages which have the best chance of breaking down the bacteria," says Dr. Nobrega.

"The more samples we are able to obtain, the better our chances of finding the best phages for the job."