Phage Therapy

Existing antimicrobial therapies are failing us. New chemical antimicrobials have not been forthcoming. Heather Louise O’Donoghue asks: How do you solve a problem like antimicrobial resistance? 

Viruses are dangerous, and the fear they inspire is understandable. Ebola killed 11,300 people in Sierra Leone, Liberia, and Guinea in just two years. SARS spread globally in 2001 and killed 774 people. A particularly virulent seasonal Influenza in 2017 infected an estimated 45 million people and caused approximately 61,000 deaths in the USA. Since January 2020, COVID-19 has been spreading globally, causing economic panic, global quarantines, spiralling infections and deaths. At the time of writing (21st May 2020) there has been over 5.1 million infections and 330,000 deaths worldwide. 

Bacteria once inspired fear like this. But, in the mid-20th century, we discovered a vital weapon against them – antibiotics. Previously fatal infections were not only treatable, but ultimately curable. Recently, however, antibiotic resistance has been accelerating globally. New research is going to hold the key to addressing this threat. 

The discovery of Penicillin towards the end of World War II is a famous story. Alexander Fleming was a Scottish microbiologist who had served with the Army Medical Corps throughout World War I. While working at St. Mary’s Hospital in London in 1928, he left a plate of Staphylococcus aureus uncovered over the weekend. Upon returning to work, he discovered it was contaminated with the fungus Penicillium chrysogenum and that around the areas of contamination, the bacterial cells had burst. Fleming found this highly unusual and decided to keep the plate to study it further. It took 10 years for the active ingredient to be isolated – this was subsequently named Penicillin. Initially, Penicillin had to be fermented from P. chrysogenum, so mass production was difficult. It was, therefore, limited to treating the wounded on the battlefields of World War II. Once the war was over, fermenting was scaled up and Penicillin became widely available. It was a roaring success. Over the next 40 years, many new classes of antibiotics were discovered, with the majority being produced by other microorganisms. The spectrum of antibiotics available by the early 2000s could treat a huge range of bacterial infections. Most of us have suffered from bacterial infections at one time or another – ear, chest, and urinary tract infections are the most common. However, there are lots of places we never think about getting bacterial infections, like in your mouth following dental work, or under your skin because of a small cut or graze. Antibiotics can help us to recover from all these infections. Unfortunately, antibiotics have a fatal limitation. While their targets can adapt and change, antibiotics cannot. Bacteria have the ability to evolve resistance to things that can kill them, which is how they have evaded the human immune system over tens of thousands of years. This has been understood for a long time. As early as 1967, a mere 20 years after Penicillin became widely available, strains of Streptococcus pneumoniae were identified that had acquired resistance. 

Irresponsible use of antibiotics has accelerated the development of resistance. Over- prescribing, incomplete courses, and use of antibiotics in food production has led to resistance developing across a number of bacterial families. In the USA, approximately 35,000 people die annually as a result of contracting drug-resistant infections. The World Health Organisation (WHO) declared antimicrobial resistance one of the top 10 threats to global health for 2020. Superbugs – bacteria that are resistant to multiple drugs – are now a significant threat to human health. Bacteriophage are viruses that infect bacterial cells. Some can delay bacterial growth, others burst bacterial cell walls. While we may fear many viruses, bacteria-attacking viruses are our natural allies in the fight against antimicrobial resistance. The original antibiotics came from microorganisms – why couldn’t the next generation? Dr Graham Stafford, a microbiologist in the School of Clinical Dentistry at The University of Sheffield, is one of the researchers looking to viruses to help solve this problem. Late in 2019, his research group published a paper identifying a new bacteriophage with the potential to have a therapeutic effect on the antibiotic-resistant bacterium Enterococcus faecalis. Endemic to humans, E. faecalis lives harmlessly in the digestive tract. It becomes a problem when it gets somewhere that it shouldn’t – like into a damaged tooth following a root canal. Some strains of E. faecalis can acquire resistance to Vancomycin, one of the last “line of defence” drugs currently used against antibiotic-resistant infections. Testing of wastewater turned up a new strain of a bacteriophage of the family Siphoviridae. Viruses in this family can cause E. faecalis cells to rupture. The new bacteriophage was tested against E. faecalis on a standard polystyrene testing material, followed by a cross-section of a human tooth, and finally against a systemic infection in zebra fish embryos. It proved effective – clearing the infection in each. 

You might be thinking, based on this, that this treatment will be hitting pharmacy shelves next year, and the doctor will be handing it over next time you have a chest infection. Unfortunately, it’s not that simple. While research into bacteriophage as a treatment for bacterial infections is increasing it has been limited to date. Dr Stafford put one of the challenges to this therapy very succinctly, “Maybe it’s a branding issue – I doubt many people would be too happy if their dentist told them they were going to rinse their mouth out with viruses.” Thinking about how viruses make us ill, it’s hard to imagine that anyone would be lining up to get pumped full of them. How could they believe it would make them better? 

Branding is not the only challenge. Academic interest has been increasing over the past few years, and there are a few small start-ups looking into phage therapy around Europe. But large scale investment from the pharmaceutical sector is lagging behind and while the Food and Drug Administration (FDA) have been loosening their regulations, regulators in the UK and Europe haven’t changed their position. Experimental phage therapies are not approved for use. Just because you prove the concept in an academic setting, doesn’t mean it will be developed into a commercially viable therapy. 

One of the concerns pharmaceutical companies and regulators have is resistance developing to phage therapy. According to Dr Stafford, the development of phage resistance is where the brilliance of these therapies lies. Just like the human immune system has evolved to 

protect us from bacterial infections, bacteria evolve, evading our immune system and making us ill. Bacteria can also acquire resistance to phage, but it changes their DNA, how they function, and their structure. These changes can be beneficial in fighting infections in humans. They can lead to decreased virulence, inability to evade the immune system, or increased vulnerability to antibiotics. Thus, the therapeutic approach may be targeted antibiotic therapy combined with an appropriate phage. More research is needed into the potential of phage therapy. Research, however, can’t go ahead without adequate funding. Dr Stafford explained the challenges of getting funding for this type of research “Microbiology in clinical dentistry is difficult. It’s not as much of a giant panda as S. aureas or sepsis”. Giant Pandas are notorious for receiving a lot of conservation money and effort but are probably not the most deserving. This is not to suggest that any one type of infection is more important or more deserving of research and funding. It simply means that you have to really prove your case to get funding. E. faecalis is a better candidate for research funding if it doesn’t just infect root canals. As it happens, it is also known to aggressively colonise open ulcers: the types diabetics often suffer from. This is the next step for Dr Stafford’s group – testing their novel phage in infected diabetic ulcers. It is a long way off human trials, but there is a way to test it against the next best thing. The tissue engineering lab at The University of Sheffield takes excess human skin from surgery and grows it into artificial skin. E. faecalis is cultured from the ulcers of diabetes patients at the outpatient clinic of Royal Hallamshire Hospital. The artificial skin is wounded and infected with E. faecalis. The phage from Dr Stafford’s lab will then be used to treat it and studied for therapeutic effect. It sounds a little ghoulish, but deliberately infected fake skin might be the best way to generate interest in this particular phage therapy. Viruses are our natural enemies. The ones we know about are hard to fight. The ones we don’t know about are hidden in animal reservoirs and when they spillover it can be catastrophic. They sicken us and they can kill us. They terrify us. But they can also be our natural allies in the fight against antibacterial resistance. Phage therapy as a support to antibiotics has the potential to revolutionise the way we manage antibiotic-resistant infections. Its therapeutic potential must continue to be explored if we are to win the arms race against bacteria.

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