Dr. Franklin Nobrega of the University of Southampton reveals how his team’s latest research drives ways to outperform phage therapy and revolutionize infection treatment.
As antibiotic resistance accelerates into the global health crisis, scientists are turning to an unconventional but promising solution: phage therapy. This approach utilizes bacteriophages, viruses, to naturally target and destroy bacteria, leaving human cells intact.
At the University of Southampton, researchers have made major breakthroughs to understand how bacteria protect themselves against phages and how they can overcome those defenses.
Their work focuses on a bacterial defense system called Kiwa, named after the guardian of Maori mythology. The Kiwa acts like a molecular firewall, detecting and neutralizing invading phages before taking over bacterial cells.
By revealing details about how Kiwa works and how some phages use decoy proteins to avoid it, the team has taken an important step towards developing next-generation phage therapy treatments for drug-resistant infections.
In this interview, Dr. Franklin Noverega, an associate professor at the University of Southampton and a unit of the National Institute of Health Therapy (NIHR) Southampton Biomedical Research (BRC) will explain the possibilities of phage therapy to tackle antibiotic resistance and explain the science that will help citizen science build a library of these powerful committee members.
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?
As we know today, since antibiotics were discovered, there has always been a perception that antibiotics always have an excessive appearance of resistance. Unfortunately, we have overused them in multiple areas. For example, in agriculture, food production, particularly in clinical settings due to overprescription.
Some antibiotic management programs took time to implement, and overuse continued during their delays. As a result, we are currently looking at hospital strains that are resistant to most first-line antibiotics, some even resistant to the final resortment option. This is why many people call the situation a “silent pandemic.”
We are increasingly facing bacterial infections where our existing treatment portfolio does not provide a solution. This is why alternatives like phage therapy are being revisited. It is an old treatment in terms of human discovery and use, but has not been studied extensively in the clinical setting as much as antibiotics have had since introduction.
For those who are unfamiliar, could you explain what phage is, how it differs from antibiotics, and how it attacks infection?
Phage stands for bacteriophage, which literally means “bacteria eating people.” They are viruses that infect bacteria but do not infect humans. These small viruses replicate by infecting bacterial hosts and produce more viral particles than they infect other bacteria.
When taking antibiotics, it is necessary to maintain stable concentrations in the body by administering them regularly. One advantage of phages is that they replicate at the site of infection and may increase the number during treatment. However, as clinical studies show, phages must also be administered in multiple doses.
Importantly, phages can function synergistically with antibiotics. Bacteria can develop resistance to phages in the same way as antibiotics, but the mechanisms involved can make antibiotics more susceptible to antibiotics again. This synergy is one of the most powerful aspects of combining these treatments, despite it still being classified as experimental medicine in the UK and many other countries.
In your research, we explored a bacterial defense mechanism called Kiwa. Can you explain how this works and why it is so effective against phage attacks?
“Bacterial immunity” is a relatively new term, but the concept has been around for a long time. This is the basis of many of the biotechnology tools we use today.
For example, when producing biology, whether in the food industry or in other sectors, bacteria can serve as factories for making useful products. Not all bacteria are harmful, many have been modified, removing any other protective elements against phages. These defenses are common in what is known as the “defense islands” of the bacterial genome.
CRISPR is perhaps the best known antiphage mechanism, but there are many others. In fact, more than 300 anti-PHEGE 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, the primary line of defense against phages. Kiwa-related genes produce proteins that integrate into the membrane and form a network or armor that detects phage docking. This leads to 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 can avoid thorns. Understanding both is important. In some contexts, like human infectious diseases, we want to make phages a successful one. In others, such as in the production of dairy products, phages are harmful because they can destroy the starter cultures of bacteria used to make products such as cheese and yogurt. So we will study both ways that phages help bypass bacterial defenses and how to enhance those defenses when necessary.
Phage developed a clever tactic using a decoy protein known as GAM. How does this work to bypass Kiwa?
GAM is DNA mimic. This is a protein that mimics the shape of DNA. Many viruses produce decoy-like proteins to bypass bacterial protection. I sometimes compare it to a fighter jet and release decoys to mislead incoming missiles. Similarly, these proteins help phages avoid detection and continue to infect bacterial cells.
How does your team discovery open the door to new ways of engineering phages and remove bacterial protection?
We found that many preventive proteins have a wide range of uses. For example, DNA mimetics were first discovered in connection with another bacterial defense mechanism: a restriction correction system.
A single bacterial cell can have 5-7 different anti-permeasure systems. Once we can identify the optimal combination of proteins to turn off these defenses, we can design next-generation phage therapies that explain this complexity.
Interestingly, mobile gene elements (plasmids) that are usually associated with antibiotic resistance also carry several mobile genetic elements. This means that the diffusion of anti-permeable resistance can be wider than we thought. Therapeutic toolkit can be expanded by identifying phages that naturally carry useful defense proteins, or by equipping such proteins.
The NHS spends around £180 million per year on drug-resistant infections. Do you think phage therapy will become a widely used treatment in the coming years?
Since January this year, Phage therapy can be used in the UK under a compassionate use scenario. The main requirement is that phages must be produced to GMP (good manufacturing) standards. This is the same quality control used for injectable drugs.
In Europe, clinical grade phages (like my lab and others in the UK) are easier to use, but using the NHS requires GMP level production. Currently, there is no dedicated GMP phage facility in the UK, so phages must be produced elsewhere before use.
I am part of my efforts to build a GMP site in Southampton, with other groups across the country working on similar projects. The company aims to start GMP-level production by early 2026.
Nowadays, phages can already be requested from infectious disease experts through a central process. The NHS then evaluates each case, taking into account factors such as reduced antibiotic needs, shorter hospital stays, and shorter staff time, taking into account other factors. For patients, this could mean early access to effective treatment and quality of life, especially for those who have endured ineffective antibiotic therapy for months or years.
Do you think UK regulations are lagging behind the pace of phage research?
The UK has adopted a cautious approach to experimental drugs, and clinical trials are of course necessary. The problem is not the regulations themselves, but that government funding does not coincide with the urgency perceived by these regulations.
Let’s say people are dying of antibiotic resistance, but are acknowledging that they don’t fund the necessary clinical trials, progress. Another problem is that much of the UK’s funding for the production of GMP phages is spent overseas, for example, in Canada.
It’s not just that the law is slow. This means that the entire process is fragmented, from fundraising to execution. Leadership goals and operational management are not aligned. This is the Frankenstein system.
You invited the public to send dirty water samples. How important is the contribution of citizens to phage research and how do you hope this will go ahead with your work?
Citizen science is incredibly valuable. We first launched this idea at the Royal Society and almost immediately overwhelmed with 10,000 samples. We had to quickly build our infrastructure just to handle everything.
Thinking about phage therapy can help distinguish between “drug substances” (the phage itself) and “drugs” (the therapy given to patients who must meet GMP standards). Civic scientists can help discover drug substances – phages – by collecting samples from diverse environments.
This allows us to build a more comprehensive phage collection, covering not only our region, but the entire UK and even internationally. We are now becoming the first division of Environmental, Food & Rural Affairs (DEFRA) certified collection sites for the handling of controlled phage samples.
This global approach is important because bacterial infections do not have boundaries. For example, patients in our support hospitals have returned from Morocco with a bacterial infection that is resistant to all known antibiotics. Having a diverse library of phages makes it more likely that you will find effective treatments in such cases.
What will the next 12 months look like for your research?
There are two main focuses. First, we are developing European-funded clinical trials to test the safety and efficacy of phage therapy. Writing and securing sponsorships for this is a major challenge, but it is essential.
Second, we are working to establish a GMP phage production site that bridges the large gap in its ability to provide UK phage therapy on a large scale.
The Citizen Science Program is also expanding. We want to see “reverse socialization.” There, we are the younger generations who educate us about phage research and pass that knowledge on the older generation. We already support high school and university teachers running phage isolation programs and implementing similar initiatives in the US.
In doing so, we want to encourage more students to pursue research in this field.
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