New insights could help phages defeat antibiotic resistant bacteria

Discoveries by Southampton researchers on how bacteria defend themselves against viruses could be key to tackling antibiotic resistance.

Finding new ways to fight bacteria is a pressing concern due to the growing threat of antibiotic resistance.

Antibiotic resistant bacteria are not killed by antibiotics. Viruses that attack bacteria, known as phages, offer a promising alternative.

Unpicking how bacteria protect themselves against phages, and how phages overcome these defences, could be a significant step in defeating antibiotic resistant bacteria.

Bacterial defences

Phages only attack bacteria, and are harmless to human cells.

They look like a syringe with spider legs. They inject their DNA into the bacterial cell. In this way, they hijack it, making it produce more copies of the virus. The cell then bursts open and releases the new phages to attack other bacteria.

New research, published in the journal Cell, is the first to describe how a bacterial defence mechanism against phages, called Kiwa, works.

Dr Franklin Nobrega is an Associate Professor at the University of Southampton. His work forms part of the NIHR Southampton Biomedical Research Centre (BRC)’s Microbiology, Immunology and Infection theme.

“In Māori mythology, Kiwa is a divine guardian of the ocean and its creatures,” he says. “In bacteria, Kiwa also acts as a guardian, defending against phages, and are one of the most common defence 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. This alerts KwaB, which binds to the phage DNA and turns it off before it can take over the cell.

Using a ‘decoy’

Some phages have evolved a clever way to break through this two-step security system. They release a ‘decoy’ protein called Gam. This tricks KwaB into attacking them, while the real phage DNA slips through.

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.”

Tackling a global threat

Antibiotic resistance 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 that have the potential to overcome bacterial defences. They have identified over 600 different types to date.

They are inviting people to collect a sample of dirty water and post it into the lab for analysis. Dirty water provides the perfect breeding ground for bacteria and phages.

“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 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.