Dr Franklin Nobrega of the University of Southampton reveals how his team’s latest research is pushing phage therapy forward to outwit antibiotic-resistant bacteria and revolutionise infection treatment.
As antibiotic resistance accelerates into a global health crisis, scientists are turning to an unconventional but promising solution – phage therapy. This approach harnesses bacteriophages, viruses that naturally target and destroy bacteria while leaving human cells unharmed.
At the University of Southampton, researchers have made a significant breakthrough in understanding how bacteria defend themselves against phages, and how those defences can be overcome.
Their work focuses on a bacterial defence system called Kiwa, named after a guardian from Māori mythology. Kiwa acts like a molecular firewall, detecting and neutralising invading phages before they can take over the bacterial cell.
By uncovering the details of how Kiwa works and how some phages use decoy proteins to evade it, the team has taken a critical step toward developing next-generation phage therapy treatments for drug-resistant infections.
In this interview, 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, explains the science behind Kiwa, the potential of phage therapy to tackle antibiotic resistance, and how a citizen science is helping to build a nationwide library of these powerful bacterial predators.
Antibiotic resistance is increasingly described as a global emergency. From your perspective, why have we reached this point, and why is it so important to find alternative treatments?
Since the discovery of antibiotics as we know them today, there’s always been awareness that resistance would eventually emerge from overuse. Unfortunately, we’ve been overusing them in multiple areas – for example, in agriculture, food production, and, most notably, in clinical settings through overprescription.
Some antibiotic stewardship programmes took time to be implemented, and during that delay, overuse continued. As a result, we now see hospital strains resistant to most first-line antibiotics, and some are even resistant to last-resort options. This is why many refer to the situation as a ‘silent pandemic.’
We are increasingly facing bacterial infections for which our existing treatment portfolio offers no solution. This is why alternatives like phage therapy are being revisited. Although it’s an old therapy in terms of discovery and use in humans, it has not been as extensively studied in clinical settings as antibiotics have since their introduction.
For those unfamiliar, could you explain what phages are, how they differ from antibiotics, and how they attack infections?
Phages are short for bacteriophages, which literally means ‘bacteria eaters.’ They are viruses that infect bacteria but do not infect humans. These tiny viruses replicate by infecting their bacterial hosts, producing more viral particles that go on to infect other bacteria.
When we take antibiotics, we need to maintain a steady concentration in the body by taking doses at regular intervals. One advantage of phages is that they can replicate at the site of infection, potentially increasing their numbers during treatment. However, as clinical studies show, phages also need to be administered in multiple doses.
Importantly, phages can work synergistically with antibiotics. Bacteria can develop resistance to phages, just as they do to antibiotics, but the mechanisms involved can sometimes make the bacteria more susceptible to antibiotics again. This synergy is one of the most powerful aspects of combining these therapies, even though phage therapy remains classed as experimental medicine in the UK and many other countries.
Your research explored a bacterial defence mechanism called Kiwa. Could you explain how this works and why it’s so effective against phage attacks?
‘Bacterial immunity’ is a relatively new term, but the concept has been around for a long time. It’s the basis for many of the biotechnological tools we use today.
For example, when producing biologics, whether for the food industry or other sectors, bacteria can serve as factories to make useful products. Not all bacteria are harmful, and many have been modified to remove elements that would otherwise defend them against phages. These defences are often found in what we call ‘defence islands’ in the bacterial genome.
CRISPR is perhaps the most well-known anti-phage mechanism, but there are many others. In fact, more than 300 anti-phage systems have been identified, particularly in clinically relevant pathogens such as E. coli, Salmonella, Klebsiella, and Acinetobacter.
We studied Kiwa in E. coli because it was particularly interesting – it was associated with the bacterial cell membrane, which is the first line of defence against phages. Kiwa-related genes produce proteins that integrate into the membrane, forming a network or armour that detects phage docking. This triggers an alarm response, leading to the decoration of incoming phage DNA in a way that prevents the infection from progressing.
We also studied how phages evade Kiwa. Understanding both sides is important. In some contexts, like human infections, we want phages to succeed. In others, such as dairy production, phages are harmful because they can destroy bacterial starter cultures used to make products like cheese or yoghurt. So we study both how to help phages bypass bacterial defences and how to strengthen those defences when needed.
Phages have developed a clever tactic using a decoy protein known as Gam. How does this work to bypass Kiwa?
GAM is a DNA mimic – a protein that imitates the shape of DNA. Many viruses produce such proteins as decoys to bypass bacterial defences. I sometimes compare it to a fighter jet releasing decoys to mislead incoming missiles. In the same way, these proteins help the phage evade detection and continue infecting the bacterial cell.
In what way do your team’s discoveries open the door to new ways of engineering phages to outsmart bacterial defences?
We’re realising that many anti-defence proteins have broad applications. DNA mimics, for example, were first discovered in relation to restriction-modification systems, which are another bacterial defence mechanism.
A single bacterial cell can have five to seven different anti-phage systems. If we can identify the best combinations of proteins to turn off these defences, we can design next-generation phage therapies that account for this complexity.
Interestingly, some mobile genetic elements – plasmids – that we usually associate with antibiotic resistance also carry anti-phage systems. This means that the spread of anti-phage resistance may be wider than we thought. By identifying phages that naturally carry useful anti-defence proteins, or by equipping them with such proteins, we can expand our therapeutic toolkit.
The NHS spends around £180m annually on drug-resistant infections. How feasible do you think it is that phage therapy becomes a widely used treatment in the coming years?
Since January this year, phage therapy can be used in the UK under compassionate use scenarios. The main requirement is that the phages must be produced to GMP (Good Manufacturing Practice) standards – the same quality control used for injectable drugs.
In Europe, clinical-grade phages (like those my lab and others in the UK can produce) can be used more easily, but GMP-level production is needed for NHS use. Right now, the UK does not have a dedicated GMP phage facility, so phages must be produced elsewhere before use.
I’m part of an effort to build a GMP site in Southampton and other groups around the country are working on similar projects. We aim to start GMP-level production by early 2026.
Currently, phages can already be requested by infectious disease specialists through a central process. The NHS will then assess each case, considering factors like reduced need for antibiotics, shorter hospital stays, and less staff time, to evaluate cost-effectiveness. For patients, this could mean earlier access to effective treatments and a better quality of life, especially for those who have endured months or even years of ineffective antibiotic therapy.
Would you say UK regulations are lagging behind the pace of phage research?
The UK takes a cautious approach to experimental medicine, and clinical trials are understandably required. The problem isn’t so much the regulations themselves, it’s that government funding doesn’t match the urgency recognised by those regulations.
Suppose we acknowledge that people are dying from antimicrobial resistance but don’t fund the necessary clinical trials, progress stalls. Another issue is that much of the UK’s funding for GMP phage production is spent overseas, for example, in Canada, even though we already have the expertise here.
It’s not just about legislation being slow; it’s that the entire process, from funding to execution, is fragmented. Leadership goals and operational management don’t align – it’s a bit of a “Frankenstein” system.
You’ve invited the public to send in dirty water samples. How important are citizen contributions to phage research, and how do you hope this will advance your work?
Citizen science is hugely valuable. We first launched this idea at the Royal Society and were overwhelmed with 10,000 samples almost immediately. We had to quickly build infrastructure just to handle them all.
When thinking about phage therapy, it helps to distinguish between the ‘drug substance’ (the phages themselves) and the ‘drug product’ (the prepared therapy given to a patient, which must meet GMP standards). Citizen scientists can help discover the drug substance – the phages – by collecting samples from diverse environments.
This allows us to build a more comprehensive phage collection, covering not only our region but the whole UK and even internationally. We’re now becoming the first Department for Environment, Food & Rural Affairs (DEFRA) certified collection site for controlled phage sample handling.
This global approach matters because bacterial infections have no borders. For example, a patient at a hospital we support returned from Morocco with a bacterial infection resistant to all known antibiotics. Having a diverse library of phages gives us a much better chance of finding an effective treatment in such cases.
What does the next 12 months look like for your research?
We have two main focuses. First, we’re developing a European-funded clinical trial to test the safety and efficacy of phage therapy. Writing and securing sponsorship for this is a big challenge, but it’s essential.
Second, we’re working to establish the GMP phage production site that would fill a major gap in the UK’s ability to deliver phage therapy at scale.
We’re also expanding our citizen science programme. We want to see ‘reverse socialisation’ – where younger generations we educate about phage research then pass that knowledge on to older generations. We already support high school and college teachers to run phage isolation programmes, and run similar initiatives in the US.
By doing so, we hope to inspire more students to pursue studies in this field, which we believe will remain highly relevant for years to come.
