Bacterial self-defense may hold clues to tackling antibiotic resistance

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 defences, 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 published today [28 July] in the journal Cell is the first to describe how a bacterial defence mechanism against phages, called Kiwa, works.

In Māori mythology, Kiwa is a divine guardian of the ocean and its creatures. In bacteria, Kiwa also acts as a guardian, defending against phages, and are one of the most common defense mechanisms bacteria have."

Dr. Franklin Nobrega, Associate Professor at the University of Southampton and National Institute for Health and Care Research (NIHR) Southampton Biomedical Research Centre (BRC) Unit

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 defence 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 defences of bacteria. But just as tech companies adapt by releasing their latest update 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 collecting phages which have the potential to overcome bacterial defences, and have identified over 600 different types to date.

They are inviting people to collect samples of dirty water (the perfect breeding ground for bacteria and phages) and post it into the lab for analysis.

"By improving our understanding of how these defence 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."

The paper Kiwa is a membrane-embedded defence supercomplex activated at phage attachment sites is published in Cell and is available online.

The research was funded by The Royal Society, Wessex Medical Research, Welch Foundation, National Institutes of Health and Simons Foundation. The Phage Collection Project is supported by the NIHR Southampton BRC Unit.