Antibiotic resistance develops when bacteria become less sensitive to antibiotics, rendering them less effective or ineffective at killing bacteria and treating infections. We urgently need new therapeutic strategies to combat...
Despite representing the most abundant entity on earth, outnumbering every other species in the world combined (including bacteria!), bacteriophages are relatively unknown to the everyday person. Even in the current era where viruses have become the centre focus of media attention, phages have remained in the shadows since they do not pose a threat to humans – out of sight, out of mind! However, this aversion for humans, and their absolute affinity for bacteria, open an enormous range of opportunities where phages can be utilised to the advantage of humans.
Bacteriophages, or phages for short, are bacterial viruses that exclusively infect and replicate within bacteria or archaea. Translating from their Latin nomenclature to “bacteria eater”, phages selectively target bacteria where they bind to a specific cell surface receptor, enzymatically degrade the outer cell layer of the host, and inject their genome into the cytosol to begin the phage infection process. The structure of bacteriophages follows that of the characteristic viral layout, composed of a protein capsid that encapsulates a single or double-stranded DNA- or RNA-based viral genome. The structure of the protein capsid can range in complexity from a simple filamentous form, an icosahedral head without a tail, to a complex icosahedral (20-sided) head with a tail.
Phage tropism, which is the ability of phages to bind to a specific bacterial receptor expressed on the surface, means phages are tightly regulated in which bacterial species they can infect and destroy. This property makes them extremely useful for human applications as they can be targeted to a specific bacterial type of interest while sparing those bacteria that are beneficial.
This has led to the use of phages in an array of biotech, agricultural and cosmetic applications, where they act to eliminate infectious bacteria or control bioburden during manufacturing.
The treatment of bacterial infections in humans and animals is a leading use case for bacteriophages. Phage therapy emerged at the start of the 20th century with widespread research and medical use in Russia and Georgia, remaining in use to this day in these nations. The therapy exploits the specificity of phage to a particular bacterium, and by giving it locally or systemically to patients, can be used to eliminate a pathogenic infection. The initial interest in phage therapy in Western countries was quickly diminished following the discovery and mass production of penicillin
and subsequent antibiotics. However, in recent years, phage therapy has garnered new attention due to the potential to overcome the increasingly concerning rise of antibiotic-resistant bacteria – deemed in 2016 by the United Nations General Assembly to be “the greatest and most urgent global risk”. The interest in phage therapy has been fuelled further by successful compassionate use studies for the treatment of infections, ranging from necrotizing pancreatitis complicated by a multi-drug resistant Acinetobacter baumannii infection to chronic otitis (ear inflammation) caused by antibiotic-resistant Pseudomonas aeruginosa. The use of phage therapy in the United Kingdom received a welcome boost in recent years after the successful treatment of a child with a cystic fibrosis-related infection that persisted and spread to many locations even after a double lung transplant and strong antibiotics.
Bacteriophages have a range of intrinsic properties that make them a promising candidate for future therapies. Namely, phages are capable of “auto-dosing”, the ability of phages to self-replicate, expand the phage population, and essentially increase the bacteria-killing capacity themselves! Bacteriophage therapy is also inherently non-toxic due to the basic structure of phages that consist of protein and nucleic acid bundles. This presents a major advantage over antibiotics that commonly cause side effects (1 in 10 people) and allergic reactions (1 in 15 people). Of course, as a foreign agent, phages have the potential of eliciting a harmful immune response in the host, however so far there is little evidence that this is a meaningful concern in pure phage therapies manufactured to a high standard.
Research continues to reveal the importance of our gut microbiota for human health, including playing a role in the normal development and functioning of the human body, especially for the priming and maturation of the adaptive immune system. Traditional antibiotics can drastically perturb the beneficial microbiome of the gut which has coined the phrase “antibiotic scarring” to describe the altered diversity, resistance, and composition of the microbiome that occurs after a course of antibiotics. In contrast, phage therapy can utilise singular phages to target a specific type of infectious bacteria, while preserving the surrounding beneficial microbiota.
In addition to holding great promise in medicine, bacteriophages are currently more widely used in other applications, from the food industry to cosmetics.
Phage use in agriculture and food sectors
The UK and USA have deemed phages “safe for consumption” and their benefits can now be used to control microbial growth in the food and agriculture industries. Phages can be used at all stages of the agriculture supply chain to control microbial contamination and prevent food spoilage through deployment in three sectors: primary production, biosanitisation, and biopreservation. In primary production, phages can be added to crops at the pre-harvest stage to prevent crop disease and therefore improve growth and yield. During harvest, manufacturing and processing, bacteriophages can be used as a method of biosanitisation to prevent and reduce bacterial biofilms forming on the surface of the equipment. In the final step of the supply chain, phages can be added to food products as a preservative to increase shelf-life, with several phage biopreservatives currently on the market. A Fixed Phage study demonstrated that a cocktail of phages against a P. fluorescens spoilage strain extends the freshness of salad by 50% (1 day) when immobilised to a plastic insert added to the packaging. Further optimisation of the phage cocktail is expected to increase the shelf-life even further.
Phages in Animal Health
Phages can be used in an array of applications to improve animal health in both livestock and companion animals. Applications include the use as a prophylactic to prevent disease, as an antibacterial to treat an active infection, as well as in the biosanitisation of animal feeds and equipment. Globally it is estimated that 66% of antibiotics are used in farm animals and this is a major driver of antimicrobial resistance. As in humans, phage therapy offers the potential to overcome antibiotic-resistant bacteria in animals and has been achieving positive results in the treatment of various bacterial diseases in cattle, pigs and fish, to name a few. Phages offer the benefit of immobilisation onto animal feed to prevent spoilage or to target the antimicrobial to hard-to-treat animals, such as fish. A Fixed Phage study developed a bacteriophage solution targeting Flavobacterium that was immobilised onto small trout feed pellets, while phage-treated feed was able to almost entirely prevent the death of shrimps following lethal infection. Phage treatment of feed pellets in aquaculture avoids the need to dose the entire fishpond with antibiotics, preserving the beneficial flora in the local environment.
Non-medical use of bacteriophages in human health
While phage therapy for medical use continues to progress through clinical trials with great promise, the benefits of bacteriophages are already available to the consumer in other forms. Commercial products containing bacteriophages are currently marketed as prebiotic supplements. These supplements aim to select beneficial bacteria throughout the small and large intestines to promote healthy gastrointestinal and immune functions. It is reported that the gut benefits can be increased even further by combining phage supplements with probiotics to increase the colonisation of the beneficial bacteria delivered.
Phages can be incorporated into cosmetic products to improve skin health where harmful bacteria are involved, while not disturbing the beneficial skin microbiome. Phage-based cosmetics have improved clear skin by targeting the acne-causing C. acnes strain. Indeed, a Fixed Phage study showed that cream containing immobilised bacteriophages that target C. acnes could eliminate the full bacterial load of C. acnes on the skin.
This provides an innovative solution for addressing skin conditions while preventing the side effects associated with systemic antibiotic use, such as the serious side effects of depression and birth defects associated with Accutane.
Fixed Phage leads the design, development and commercialisation of applications which use stabilised phage to solve bacterial challenges. With over a decade of experience in the sector, our patented technology can be used across an array of applications to minimise risk and sustainably solve bacteria problems. From agriculture to cosmetics, we have the expertise to isolate, identify and supply bespoke phage cocktails across a wide range of applications. Our technology utilises the immobilisation of phages to compatible surfaces to increase stability and allow for storage at ambient temperatures for years. This provides an affordable, robust and targeted solution to microbial prevention or removal.
We collaborate with partners across the world to develop solutions for their bacterial issues that are sustainable, naturally based and completely harmless to plants, animals and humans. If your process is being challenged by bacterial contamination, get in touch to learn more about our partnership approach to developing your solution.
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