An army of viruses against superbugs: Science revives phages to combat antibiotic resistance

A great microscopic battle is brewing: bacteria-eating viruses against antibiotic-resistant superbugs. The World Health Organization (WHO) has classified resistance to these drugs as “one of the greatest threats to global health” — it could kill 208 million people in 25 years — and science has been working to find a solution from different angles. One of these has been to rescue phage therapy from history, which consists of using bacteriophage viruses (phages) to exterminate resistant bacteria.

Thousands of treated patients have demonstrated their therapeutic potential over the last century, but the still-limited knowledge of the vast population of phages on the planet and the complexity of adapting this strategy to the current regulatory framework mean that phage therapy has not yet taken off. The scientific commitment to building an army of phages against superbugs, however, remains firm and an international consortium has just received €1.2 million ($1.24 million) from the European Union to deepen our knowledge of these bacteria-eating viruses.

The history of phage therapy spans more than a century: from the beginning, the idea was to use the machinery of these viruses — capable of infecting or killing bacterial cells without harming the rest of the organism — to destroy the microbes causing serious infections. That was the plan. And it worked. But with the discovery and expansion of penicillin in the middle of the last century, phage therapy fell into oblivion in the West although in Eastern Europe and the Soviet Union, research with it continued. Its global renaissance has arisen precisely when some antibiotics have reached their ceiling and a handful of bacterial families have become resistant to all the drugs available to annihilate them.

The scientific community has seen an opportunity in phage therapy and research has been stepped up. A Lebanese review published a few weeks ago in the Journal of Global Antimicrobial Resistance confirmed that phage therapy was growing in the United States, Europe, and the Middle East. Another Japanese study on the current state of this therapeutic approach agreed and provided a couple of paradigmatic cases that crystallize that the scientific commitment is serious: in Belgium, for example, a national phage bank has been established and the University of California, in the United States, has founded the Center for Innovative Phage Applications and Therapeutics.

María del Mar Tomás, a microbiologist at the A Coruña University Hospital Complex (CHUAC) in Spain and coordinator of the international project from the A Coruña Biomedical Research Institute (Inibic), explains that phages are found everywhere in the environment. Wherever there is a bacteria, these viruses will be there, numbering in the trillions and trillions: it is estimated that there are 10 to the power of 30 phages in the ocean. Those that interest scientists as a therapy are the lytic phages, which recognize the bacteria and kill it immediately. “The phage arrives, recognizes the bacteria and, in order to be able to embed itself inside it, needs receptors. Once it binds to these receptors, it integrates its DNA and begins to use the bacteria’s machinery to replicate its proteins and make tiny viruses. When there is a complete virus, the bacteria explodes and lysis occurs [decomposition of the microbe].”

The scientists’ initial plan was to use phages to kill bacteria, but they have also discovered that these viruses can enhance antibiotics. “It has been seen, and that is why Europe is beginning to consider lytic phages as medicine and sees potential in them, the synergistic effect with antibiotics. Phages can cause a resensitization of bacteria to these medicines and that would allow us to again use those antibiotics that we have lost,” says Tomás.

The treatments are highly personalized, based on a preparation of a single phage or a cocktail of several viruses selected ad hoc against a specific bacteria. In most cases treated, they were people who had already exhausted all therapeutic alternatives, such as a patient with cystic fibrosis and a disseminated infection by Mycobacterium abscessus who was successfully treated with a cocktail of three phages after a lung transplant: the treatment eliminated the infectious strain and improved the wound from the operation, liver function, and skin lesions associated with the infection.

Specifically, Cristina Berastegui, from the Vall d’Hebron Research Institute (VHIR) pulmonology research group, participated in a study analysing 20 similar cases of mycobacterial infection treated with phages and concluded that more than 50% of the patients improved. “Phages are not a panacea, but they offer a promising future for infections caused by multi-resistant bacteria,” says the pulmonologist.

There are also studies that have demonstrated the potential of this therapeutic approach to treat sepsis, urinary tract infections, osteomyelitis, or pneumonia, among other ailments. Tomás assures that in topical infections, on the skin, such as ulcer overinfections or in burns, the efficacy is around 90%. “There is a French group that uses phages in prosthetic infections during the operation itself and is having 80% to 90% success. Where we have less success is in sepsis and cardiovascular infections,” says the microbiologist.

A scientific review published in The Lancet Infectious Diseases in 2022 analyzed more than 2,200 patients treated with phages in the first two decades of this century and concluded that in 79% of cases there was clinical improvement, and in 87% of patients treated with bacteriophages, the bacteria they were targeting was eradicated. In addition, adverse effects were only recorded in 7% of cases and all were mild.

Among the advantages of phages, experts highlight their high specificity, meaning that they are highly targeted to a specific bacteria, which will prevent damage to the body’s normal flora. There is therefore less risk of side effects, such as secondary infections caused by antibiotic therapy, which tends to attack a broader spectrum of microbes and sweep away the bad ones, but also some good ones, which de facto implies damage to the intestinal microbiome.

Persistent bacteria

In the war against antibiotic resistance, Tomás also highlights the potential of phages, but admits that these viruses will not be the ones to fight the final battle against superbacteria. In fact, in this never-ending evolutionary race, resistant microbes also learn to avoid the attack of phages, she assumes. “Belgian researchers have carried out an observational study with 100 patients with different infections in different locations. They have simply used 26 phages, pre-adapting them to the bacteria responsible for the infection, and have achieved an eradication success rate of between 65% and 77%, with clinical improvement. But there has been a 40% innate resistance of the bacteria to the phage. In other words, the bacteria have innate mechanisms of resistance to antibiotics and phages and to any stress. Therefore, looking for common areas in these molecular mechanisms of response to stress would allow us to develop a treatment with greater potential,” the researcher suggests.

In the case of the international project coordinated by Inibic, the objective is to test phages against a very particular type of microbe: persistent bacteria. “After years studying the response of bacteria to infection by phages, we have seen several molecular mechanisms of resistance that consist of telling the bacteria to enter a state of latency. And we think that we could go against that, against the development of persistent bacteria responsible for chronic infections,” says Tomás.

Scientists have identified bacteriophages capable of acting against these persistent bacteria that, in any stressful situation, become invisible and escape attack by any agent that wants to eliminate them, be it antibiotics or phages. “I think that if we manage to eradicate this type of population, we eliminate the infection completely,” explains Tomás. The project plans to create a bank of phages and persistent bacteria, as well as testing combinations of antibiotics and phages to neutralize these super-resistant microbes.

Loose ends

Phage research is gaining momentum, but there are still loose ends that trip up researchers. Thus, while there is observational evidence of success stories and data that phage therapy is a safe therapeutic approach, there is also skepticism about the efficacy results within the scientific community. A review of these treatments explains that, “despite compelling observational evidence, modern clinical trials, while consistently demonstrating safety, have so far not consistently demonstrated efficacy” and points out that this limited efficacy “arises from clinical and microbiological challenges unique to phage therapy.”

One factor that weighs heavily is the fact that it is a highly personalized treatment, where the phage or phage cocktail is used for a very specific bacteria in a very specific patient. Not all patients require the same dose or the same types of phages. In addition, the preparations “will require continuous adjustments and reformulation to adapt to changes in bacterial populations and resistance patterns,” the authors of the review explain. The number of clinically useful phages in the environment does not help either: “It would be impossible to subject each phage, or combination of phages, to clinical trials for a single type of infection, much less for the variety of bacterial infections to which the phages could be applied,” the article agrees.

The reality of these living medicines clashes with the rigidity of the regulatory framework, which can lead to delays in the approval of treatments and uncertainty when it comes to standardizing therapies. And all of this, like a kind of domino effect, also encourages the pharmaceutical industry's reluctance to invest in these approaches.

A review notes, however, that knowledge about phages is still limited and that the full range of interactions between viruses and the bacteria in which they are embedded is not fully understood, for example. The authors also raise “safety concerns”: “Phages are complex biological entities and can theoretically transfer harmful bacterial genes (such as antibiotic resistance genes) between bacteria or trigger adverse immune responses,” they stress.

The authors of the article in The Lancet Infectious Diseases, however, clarify that, “although phages can induce a direct response from the immune system, there is no evidence that they can cause damage to human cells.” They clarify that, although phages can self-amplify, causing the death of bacteria, they do not replicate endlessly: this growth process stops when the bacteria they target disappear.

The experts consulted agree on the need to properly regulate the use of this therapeutic strategy — in Spain it is used, above all, for compassionate use or in contexts of scientific studies — in order to have phages more easily available and exploit their potential to 100%. To guarantee the quality of phage cocktails, Tomás advocates creating a national network of phage therapy in advanced therapy centers. That is, preparing these treatments in highly specialized scientific laboratories, such as those where CAR-T therapy is manufactured, an immunotherapy that consists of extracting lymphocytes from the patient, genetically modifying them so that they recognize tumor cells, and reinfusing them into the patient.

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