Bacteria plays a crucial role in maintaining the ecosystem balance. However, there are few species of bacteria that can cause several infectious diseases (such as strep throat, salmonellosis, tuberculosis, whooping cough). These are mainly transmitted through air, water, living organisms, and food. Further, the spread of infections to a larger population is attributed to the potential factors like pathogenicity, infectivity, and bacterial abundance in the environment. During the early 19th century, there was a surge in the cases of infectious diseases (including cholera, diphtheria, typhoid fever, plague, tuberculosis, typhus, scarlet fever, pertussis, syphilis, and many more) due to the spread of bacterial infections via species (including Acinetobacter, Pseudomonas aeruginosa, and Escherichia coli), which led to the increase in need for an effective mode of treatment. As a result, in 1928, antibiotic agents were introduced to the world, with the discovery of Penicillin. This discovery led by Alexander Fleming, started a new era in medicine, and eventually saved millions of lives. However, over the last three decades, a different challenge has surfaced in the antibiotic therapeutics’ domain. The overuse of antibiotics has resulted in the emergence of multi-drug-resistant bacteria. In fact, resistance to antibiotics has now become one of the major challenges for the pharmaceutical industry, which has prompted the innovators to come up with the novel bacteriophage therapy.
Bacteriophages are viruses that have the ability to infect and kill the bacteria without affecting human or animal cells. They act by accomplishing the natural predator-prey interaction between phage and the target bacteria. This therapy can be used alone or in combination with antibiotics, to treat various infections and disorders. Further, the potential benefits of bacteriophage therapy are that they are environment friendly and are primarily based on natural selection and can efficiently identify the infection causing bacteria as compared to antibiotics. In addition, they have the ability to replicate within the bacteria after an immediate infection, while antibiotics can only spread throughout the body and sometimes ignore the infection sites.
In order to gain more understanding related to bacteriophages and their therapy, we have highlighted the evolution and cycle of replication of bacteriophages. In addition, we have also presented the advantages, risks and challenges linked to bacteriophage therapy. Further, this chapter also presents how the future unfolds for bacteriophage therapy.
Historical Evolution of Bacteriophages
Over the two decades post the discovery of viruses, bacteriophages were first introduced to the world. In fact, it was bacteriophage research, which led to the modern concept of viruses and formed the grounds of molecular biology and emerging molecular genetics.
Frederick Twort was the first to report the elimination of bacteria using viruses, in 1915. Two years later, Felix d’Herelle, from Institute Pasteur suggested that viruses can be used as a therapy against bacterial infections. Further, in 1919, d’Herelle and his colleagues ingested a phage cocktail, in order to ensure its safety. In fact, they also administered this cocktail to a 12-year-old boy with severe dysentery. They observed that his symptoms had eventually started to disappear after a single dose. Within a few days, the boy fully recovered from his condition. However, until 1931, d’Herelle did not publish his findings.
Then, during the period 1920s -1930s, another set of innovators initiated to perform various evaluation tests to determine the efficacy of phages against bacterial infections in humans. Further, as the results of these evaluations were usually published in non-English journals, they were not adopted widely in the Western Europe and the US.
Following this, in the 1940s, Eli Lilly became the first company to produce phages for human use in the US. These phages were used to treat various bacterial infections, such as infections due to injuries and upper respiratory tract infections. However, attributing to the improper ways of storage and purification processes used, along with the selective nature of various phages, which could not be recognized at that time, the US and majority of the Europe abandoned the use of these phage therapies, marking them as a failure. However, in regions where antibiotics were not easily accessible, such as, Russia, Poland, and the Republic of Georgia, phage therapy was widely used for the treatment of various diseases.
Applications of Bacteriophage Therapy
Bacteriophages can be employed in various biotechnological applications, including food–animal agriculture, aquaculture, human and veterinary medicine, and environmental science. The applications of bacteriophages in each of the afore-mentioned domains, have been elaborated in the following section:
Food-Animal Agriculture Industry: A new class of antibacterial agent (bacteriophages) is becoming increasingly popular for use in the food industry. It is a known fact that, Food products are mainly derived from plants and animals, however, presence of microbial population in these products, has been observed as the major cause of various types of illnesses. In 2005, WHO reported death of nearly two million people due to diarrheal diseases. In fact, 25% of the food products are discarded annually due to the presence of disease-causing microbes. Although, several solutions have been thought through, the reduction of microbial load in the food industry still remains a challenge across the globe. As a result of which, bacteriophage therapy is gaining a lot of attention, as a potent antimicrobial resistant agent. In fact, the United States Food and Drug Administration (USFDA) has already approved the use of certain phages on crops to reduce the chances of diseases (such as, bacterial blight in soyabean).
Aquaculture: On the other hand,microbial diseases in aquaculture are becoming accountable for the huge economic losses. As a result of which, several bacteriophages were introduced to the market as new alternative therapy to prevent microbial infections in aqua population. In fact, pathogens such as Aeromonas salmonicida, Edwardsiella tarda, and Yersinia ruckeri, spreading bacterial infections in fish are specifically targeted by phages.
Human and Veterinary Medicine: Bacteriophages are used as an effective therapeutic tool against multi-drug resistance and biofilm forming pathogens. The phages not only effectively reduce the formation of biofilm but also inhibit the growth of phage-resistant bacterial mutants. Moreover, the therapeutic efficacy of bacteriophages against infections caused by multi-drug resistant pathogens (such as, S. aureus, E. coli, S. pneumonia and P. aeruginosa) has been demonstrated in several animal models prior to their use in humans. Thus, bacteriophage therapy may serve as a potential alternative to antimicrobials in certain cases.
Environmental Protection: Massive amount of antibiotics and waste materials that are released into the environment from medical, agriculture, and domestic industries, have resulted in the development and transmission of drug resistant bacteria in the environment. As the soil enters the food chain, the transmitted resistant bacteria threaten the antimicrobial efficacy and results in an increased risk for humans. In order to deal with this situation scientists, aim to introduce phages that could reduce the abundance of drug resistant pathogens (E. coli and P. aeruginosa) in the soil and minimize the spread of antibiotic resistant genes.
Advantages of Bacteriophage Therapy
Advantages of bacteriophage therapy over the conventional anti-bacterial agents are described below:
Bactericidal Effect: Phages affect the bacteria in such a way that the latter are unable to regain their replication capabilities, whereas antibiotics, such as tetracycline, can result in bacterial evolution leading to antibiotic-resistance.
Ability to Auto-Dose: Phages have the ability to replicate in order to kill the host bacteria. The ability of phages to replicate is also on the bacterial density. This phenomenon is known as auto-dosing where phages themselves produce the required dose.
Low Inherent Toxicity: Phages mainly consists of nucleic acid and proteins, which makes them non-toxic in nature. However, phages can result in harmful immunological responses (such asphagocytosis, cytokine responses and impact on adaptive immunity) by interacting with the immune system. In order to prevent this, a pre-defined protocol is followed while preparing the phages, so as to prevent the occurrence of allergic reactions.
Minimal Disruption of Normal Flora: Broad spectrum antibiotics (developed for a broader range of infections) are well-known to disrupt the natural gut flora while attacking the gut bacteria. However, owing to the host specific nature of phages, these can attack only a few strains of a bacterial species, resulting in minimal disruption to the gut micro flora.
Formulation and Application Versatility: Phages are quite versatile in nature, as these can be formulated in various forms, such as liquids, creams, solids and other dosage forms. In addition, they can be mixed with phage cocktails and certain antibiotics to further broaden their properties and antibacterial spectrum.
Single-Dose Potential: Bacteriophageshave a high ability toreplicate post single-dose of administration.
Low Environmental Impact: Unlike broad-spectrum antibiotics, phages have a restricted range of hosts. Phages that have been evolved to withstand extreme conditions (sunlight, drought, and extreme temperatures)can be swiftly inactivated without causing any harm to the environment.
Low Production Cost: The cost involved in the production of a phage therapy is predominated by the cost involved with the growth of a susceptible host and its subsequent purification. It’s worth mentioning that the cost involved in the growth of a host depends on the bacterial species, whereas innovators are trying to improve the cost of purification by improving the existing technologies in this domain.
Natural Occurring: Phages are naturally occurring components in the environment. Owing to which, the products incorporated with this therapy are harmless to humans.
Phage therapy has been shown to be a promising solution to tackle the increasing resistance to antibiotics. Till now, numerous studies have been performed to evaluate the potential of bacteriophage therapies, both in vitro and in vivo. Moreover, with various scientific advancements, researchers have gained better knowledge of phage-bacteria interaction, which has enabled the development of safer and more efficient phage therapy. The extensive use of phage therapy is associated with some challenges, particularly regarding the compliance of regulatory policies. In order to address challenges, such as increasing need for phage banks, development of efficient and fast phage screening methods for the identification of therapeutic phage, establishment of efficient strategies in order to tackle the infectious biofilms, set-up of phage production protocols for assuring the quality and safety of phage preparations and the guarantee of stability while storage and transportation of phage preparation, a combination of proper phage selection, effective formulation and better clinical understanding along with the familiarity with product application should be adopted.
Moreover, the wider adoption of this therapeutic approach is likely to ultimately provide an effective solution for the increasing multi-drug-resistant bacterial infections. It is also believed that with the growing need for alternatives to antibiotics, this therapeutic treatment is likely to get adopted widely.