Bacteriophages are a massively diverse group of bacterial viruses and are often cited as the most abundant organisms on the planet. Although the abundance of natural phages means that they have been used in many different applications, the development of genetically engineered bacteriophages has opened up more possibilities beyond their natural antimicrobial activity. In particular, genetically modified bacteriophages have been proposed as a powerful solution to the significant threat of antibiotic resistance.
The agriculture and food industries contribute substantially to the threat of antibiotic resistance. Livestock farming accounts for approximately 50-80% of total antibiotic use, and the animal feed industry has reported high rates of resistance to common antibiotics such as penicillin and tetracycline. The increasing number of domesticated animals also serves as another reservoir for antibiotic resistance, posing a threat to both pets and their owners. Fortunately, ongoing research has shown that genetically modified bacteriophages have the potential to address these issues, paving the way for breakthroughs in animal health.
Understanding Bacteriophages and Phage Therapy
Bacteriophages have natural antibacterial activity – they inject their genetic material into the host cell, which results in cell lysis or the disruption of metabolism and bacterial cell death. Genetically modifying bacteriophages can increase their utility, creating phages with improved efficacy, expanded host range, increased biofilm degradation, and the ability to deliver other therapies.
Genetically engineered bacteriophages are critical to the progression of phage therapy within human and animal health. Within human health, engineered phages have been used in prokaryotic therapies (antibiotic resistance, altering the gut microbiome, targeted CRISPR editing) and eukaryotic therapies (cancer therapy, gene therapy, vaccines).
Within animal health, modified phages have also been highlighted as a promising alternative to antibiotics for multi-drug resistant bacteria. This growing interest has led to increased research in the use of phage therapy in livestock and food-producing animals, as well as in veterinary practice and companion animals.
Addressing Antimicrobial Resistance with Genetically Modified Phages
The extensive use of antimicrobials in animals has contributed to the development of antimicrobial resistance, which can be transferred to humans through the food chain or direct contact. In turn, this can also reduce the effectiveness of antimicrobials for treating human disease.
As bacteriophages can infect and kill bacteria without any negative effects on human cells, they have been proposed as an alternative or complementary, treatment to antibiotics. Bacteriophages can also be engineered to overcome the limitations of antibiotic treatment. For example, a bacteriophage effective against E. coli was modified to also produce a biofilm-degrading enzyme, leading to a simultaneous attack on bacterial cells and biofilm.
Advancements in Veterinary Medicine with Genetically Modified Phages
Not only has the number of pets in households increased dramatically over the past 30 years, but more attention is also being paid to the health and well-being of these companion animals. Unfortunately, the increase in human-animal coexistence can have some negative effects. Pets are able to transmit zoonoses to humans and can also increase the spread of antibiotic-resistant bacteria.
This highlights the need for the responsible use of antibiotics in companion animals, and also the search for alternative treatments in the form of bacteriophages. Compared to livestock and farm animals, the literature surrounding bacteriophages in pets is quite sparse but some promising results have been found in dog and cat studies.
A topical bacteriophage mixture was shown to be an effective and non-toxic treatment for Pseudomonas aeruginosa, an antibiotic-resistant bacteria that causes ear infections in dogs. Bacteriophage therapy was also found to be effective in the treatment of canine and feline urinary tract infections, caused by uropathogenic E. coli. Initial findings have also highlighted the potential of phages for the treatment of the multi-drug resistant canine pathogen, Staphylococcus pseudintermedius.
Enhancing Livestock Management with Genetically Modified Phages
Livestock management is the field of animal health in which antibiotic use has been most abused, which has therefore resulted in a considerable threat. Antibiotics have been commonly used in livestock to treat infections, prevent diseases, and promote growth. However, antibiotic-resistant bacteria are more likely to emerge in animals due to their larger biomass, increasing the risk of mutations and selecting resistant bacteria.
The most common foodborne pathogens of animal origin are the bacteria Escherichia coli, Campylobacter, Salmonella, and Listeria, which usually live in the gastrointestinal tracts of livestock animals. Phage therapy has been explored targeting these, and other bacteria, in the management of poultry, bovine, and swine livestock.
Salmonellosis has become the leading cause of foodborne zoonosis, and Salmonella is the most prominent pathogen in poultry livestock. Bacteriophages and phage cocktails have been used to effectively control Salmonella, Campylobacter, E. coli, and Clostridium in poultry chickens. In bovine species, phage therapy has been explored in the control of mastitis, a common pathological condition caused by Staphylococcus bacteria. Finally, phage therapy has also been employed to control pathogenic bacteria in swine livestock, and also in the post-harvest control of pork products and processed foods.
Regulatory Landscape and Future Prospects of Genetically Modified Phages in the UK
The increased interest in phage therapy for both human and animal health raises questions regarding the legislation of genetically modified phages in the UK. Phages are classified as biological medicine, and legislation for pharmaceuticals is defined only for industrially manufactured drugs. This means that the use of phages within animals does not easily fit into existing regulations, a major obstacle limiting the development and progression of bacteriophages in animal health.
Harnessing the full power of genetically modified bacteriophages therefore requires improving the specific regulations surrounding these products, along with continued research and clinical trials. Recently, a new collaboration between UK Phage Therapy, the Centre for Phage Research at the University of Leicester, CPI, and Nexabiome has been announced. This collaboration aims to improve the provision of phages in the UK by introducing good manufacturing practices, a national phage library, and a national clinical phage centre.
The use of bacteriophages and genetically modified phages shows massive potential within all aspects of animal health, including antimicrobial resistance, veterinary medicine, and livestock management. In order to maximise this potential however, legislation surrounding phages needs to be reconsidered, along with continued research and development into the different applications of bacteriophages in animal health.