Bacteriophages — Our new weapon in the antibody war

Bacteriophages, or phages, are viruses that specifically infect bacteria. They hold promise as alternatives to antibiotics in combating bacterial infections, particularly antibiotic-resistant strains. Phages are highly diverse and target specific bacteria by injecting their genetic material, leading to bacterial cell destruction. This targeted approach is known as phage therapy and offers a potential solution for personalized treatment. Phages have applications in agriculture, food safety, and biotechnology, helping control bacterial pathogens and detect contamination. They are also valuable tools for genetic engineering and studying bacterial processes in research. Bacteriophages represent a growing field of research with exciting potential for revolutionizing recalcitrant bacterial infection treatment.

What are bacteriophages?

Bacteriophages, also known as phages, are viruses that infect bacteria. The word “bacteriophage” literally means “bacteria eater” in Greek. These viruses are highly specific and can only infect and replicate within bacterial cells.

Phages, similar to other viruses, have a complex structure consisting of a protein coat, or capsid, that encloses their genetic material. The genetic material can be either DNA or RNA, depending on the type of phage. Some phages have an additional outer envelope surrounding the capsid, which helps them attach to and enter bacterial cells.

https://www.britannica.com/science/bacteriophage

The life cycle of a bacteriophage typically involves two main stages: the lytic cycle and the lysogenic cycle.

1. Lytic Cycle: In the lytic cycle, the phage attaches to a specific receptor on the surface of a bacterial cell and injects its genetic material into the cell. Once inside, the phage takes control of the bacterial cellular machinery, redirecting it to produce more phages. The phage’s genetic material is replicated, and new phage particles are assembled inside the cell. Eventually, the infected bacterial cell lyses, or bursts open, releasing a large number of phages that can go on to infect other bacteria.
2. Lysogenic Cycle: In the lysogenic cycle, instead of immediately initiating the lytic cycle, the phage integrates its genetic material into the bacterial chromosome. This integrated genetic material is known as a prophage. The bacterial cell reproduces normally and passes on the prophage to its daughter cells during cell division. The prophage remains dormant within the bacterial genome until it is triggered to enter the lytic cycle, often in response to certain environmental cues or stresses.

https://www.researchgate.net/figure/Schematic-and-generalized-depiction-of-the-lytic-and-lysogenic-cycles-of-phage-A-Lytic_fig1_261507955

Bacteriophages are abundant in nature and can be found wherever bacteria exist, including soil, water, and the human body. They play a significant role in bacterial ecology and have been studied extensively for their potential applications in various fields, such as medicine, biotechnology, and food safety. Phages can be used as targeted agents to combat bacterial infections, as alternatives to antibiotics, in a process called phage therapy.

History and Evolution of bacteriophages

The discovery and understanding of bacteriophages have a rich history that spans several decades. Here’s a brief overview of the history and evolution of bacteriophages:

Frederick Twort

Felix d’Herelle

1. Discovery of Phages: The discovery of bacteriophages is credited to two independent researchers, Frederick Twort and Felix d’Herelle, who made their observations in the early 20th century. In 1915, Twort, an English bacteriologist, reported the presence of a filterable agent capable of infecting bacteria, which he called “filterable viruses.” Around the same time, d’Herelle, a French-Canadian microbiologist, independently observed similar phenomena and named the infective agents “bacteriophages.”
2. Structure and Molecular Interactions: In the mid-20th century, the focus shifted to understanding the molecular nature of bacteriophages. Researchers, including Max Delbrück, Salvador Luria, and Alfred Hershey, conducted groundbreaking experiments to elucidate the life cycle of phages and their interactions with bacterial cells. These studies helped establish the foundations of modern molecular biology and provided crucial insights into the mechanisms of genetic replication and recombination.
3. Phage Therapy: Following their discovery, bacteriophages were initially considered as potential tools for combating bacterial infections. In the 1920s and 1930s, d’Herelle and his colleagues conducted extensive research on phage therapy, the use of phages to treat bacterial infections. Phage therapy gained some popularity in certain regions, particularly in the former Soviet Union and Eastern Europe, but its use declined with the advent of antibiotics.
4. Phage Typing and Phage Therapy Revisited: In the mid-20th century, phage typing emerged as a method to differentiate and classify bacteria based on their susceptibility to specific phages. This technique found applications in epidemiology and bacterial strain identification. Additionally, the rise of antibiotic resistance in recent years has sparked renewed interest in phage therapy as a potential alternative or adjunct to antibiotics, leading to increased research in this field.
5. Genomic Era: With the advent of genomic sequencing technologies, researchers have been able to study phages at the molecular level more extensively. The genomic analysis of phages has revealed their incredible diversity, with a wide range of sizes, morphologies, and genetic compositions. Phage genomics has provided insights into the evolution, gene transfer mechanisms, and ecological roles of phages in different environments.

Today, bacteriophages continue to be a subject of active research, encompassing areas such as phage biology, phage-host interactions, phage therapy, biotechnological applications, and their potential role in understanding microbial ecosystems.

Role of Bacteriophages in Treatment of Diseases

Bacteriophages have gained attention for their potential therapeutic applications, particularly in the treatment of bacterial infections. Here are some key roles bacteriophages can play in disease treatment:

1. Phage Therapy: Phage therapy involves the use of bacteriophages to treat bacterial infections. Phages are highly specific in targeting and infecting bacteria, making them potential alternatives or adjuncts to traditional antibiotics. They can be used to target specific pathogenic bacteria, including those that are resistant to multiple antibiotics. Phage therapy can be administered topically, orally, or intravenously, depending on the site of infection.
2. Targeted Antibacterial Action: Bacteriophages are capable of infecting and killing specific strains or species of bacteria, leaving non-targeted bacteria unharmed. This targeted antibacterial action reduces the disruption of the natural microbial communities within the body, which is a concern with broad-spectrum antibiotics.
3. Biofilm Disruption: Biofilms are complex communities of bacteria that are embedded within a self-produced matrix. Biofilms are highly resistant to antibiotics, making infections associated with biofilms challenging to treat. Bacteriophages have shown promise in penetrating and disrupting biofilms, making them potential tools for combating biofilm-associated infections.
4. Natural Regulation of Bacterial Populations: Bacteriophages are abundant in various environments, including the human body. They naturally regulate bacterial populations by infecting and killing bacteria. This control of bacterial populations helps maintain a healthy balance within the microbiota and prevents the overgrowth of pathogenic bacteria.
5. Potential for Personalized Medicine: Bacteriophages can be isolated and selected based on their ability to infect specific bacterial strains. This opens up the possibility of personalized phage therapy, where phages can be tailored to target the specific bacteria causing an individual’s infection. This approach has the potential to enhance treatment efficacy and reduce the development of resistance.

It’s worth noting that while bacteriophage therapy holds promise, there are challenges to its widespread implementation. These include the need for comprehensive phage characterization, regulatory considerations, ensuring appropriate dosing, and conducting rigorous clinical trials to establish safety and efficacy. Ongoing research and clinical studies are crucial for further understanding and harnessing the potential of bacteriophages in disease treatment.

Current treatments — stage of development; indications

1. Phage Therapy: Phage therapy has been used in certain regions as a compassionate treatment option for patients with multidrug-resistant bacterial infections. While phage therapy is not yet widely approved or regulated in many countries, ongoing research and clinical trials are exploring its potential applications. These trials assess the safety and efficacy of phage therapy for various indications, including chronic wounds, urinary tract infections, respiratory infections, and sepsis.
2. Biofilm Infections: Bacteriophages are being investigated as potential treatments for biofilm-associated infections, which are notoriously difficult to treat with conventional antibiotics. Research is focused on developing phage-based strategies to disrupt biofilms and enhance the effectiveness of antimicrobial treatments. This area is still in the experimental and preclinical stages of development.
3. Acne: Bacteriophages that specifically target Propionibacterium acnes, the bacterium associated with acne, have shown promise in laboratory and early clinical studies. These phages have the potential to provide a targeted approach for treating acne, but further research and clinical trials are needed to determine their efficacy and safety.
4. Food Safety: Bacteriophages have been explored as natural alternatives for controlling bacterial pathogens in the food industry. Certain phages can effectively target and kill bacteria such as Salmonella, Escherichia coli, and Listeria monocytogenes. Phage-based treatments for food safety are in various stages of development and may involve phage sprays, rinses, or coatings on food products to reduce the risk of bacterial contamination.

Phage Therapy Market Potential

According to the report, the global Phage Therapy market is expected to reach USD 100.8 million by 2028, exhibiting a Compound Annual Growth Rate (CAGR) of 17.6 percent during the period 2022–2028. Major players in the market include NPO Microgen, Proteon Pharmaceuticals, Phagelux, among others, with the top three players collectively occupying approximately 25 percent of the global market share. North America and Europe are the main markets for Phage Therapy, accounting for around 60 percent of the global market share. The dominant type of Phage Therapy is DsDNA Bacteriophage, which holds a significant share of over 90 percent. The main application of Phage Therapy is in Animal Health, constituting approximately 55 percent of the market share.

https://www.databridgemarketresearch.com/reports/global-bacteriophages-therapy-market

Potential for Future

The potential for bacteriophages in the future is vast and holds promise in several areas. Here are some potential areas of development and application for bacteriophages:

1. Antibiotic Resistance: Bacteriophages can potentially provide an alternative solution to combat antibiotic-resistant bacteria. As the global threat of antibiotic resistance increases, bacteriophages offer a targeted approach to selectively kill specific bacteria while leaving the beneficial microbial communities intact. Continued research and development of bacteriophage-based therapies may help address the challenges posed by antibiotic resistance.
2. Chronic Infections: Bacteriophages show potential in treating chronic infections that are difficult to eradicate with conventional therapies. Chronic wound infections, osteomyelitis, and lung infections in cystic fibrosis patients are examples of conditions that could benefit from bacteriophage-based treatments. Further research is needed to optimize delivery methods, dosing strategies, and treatment protocols for chronic infections.
3. Prophylactic Applications: Bacteriophages could be used prophylactically to prevent bacterial infections. For instance, in high-risk environments such as hospitals or during surgeries, targeted phage interventions could help reduce the risk of infection. This preventive approach may contribute to improved patient outcomes and reduced healthcare-associated infections.
4. Agriculture and Food Safety: Bacteriophages have the potential to be used in agriculture to combat bacterial pathogens that affect crops and livestock. They can be employed to reduce the use of chemical pesticides and antibiotics in agriculture, thereby promoting sustainable and environmentally friendly practices. In the food industry, phages can be utilized to control bacterial contamination, prevent foodborne illnesses, and extend the shelf life of perishable food products.
5. Combination Therapies: Bacteriophages can be combined with other therapeutic agents, such as antibiotics or immune system modulators, to enhance treatment outcomes. Synergistic combinations of bacteriophages with conventional therapies may help improve efficacy, reduce resistance development, and provide more comprehensive treatment options.
6. Personalized Medicine and Diagnostics: Advances in genomic sequencing and phage characterization can contribute to personalized medicine approaches. Phage libraries can be developed and tailored to target specific bacterial strains or individual patient infections. Moreover, bacteriophages can be utilized as diagnostic tools to identify and characterize specific bacteria within a patient’s microbiome, enabling precise and targeted treatment strategies.

Conclusion

It’s important to note that while the potential for bacteriophages is promising and has a huge growth potential, there are still challenges to overcome. These include regulatory considerations, standardization of phage production and characterization, ensuring safety and efficacy through rigorous clinical trials, and developing practical delivery mechanisms. Continued research and collaborative efforts will be crucial in unlocking the full potential of bacteriophages for future applications in medicine, agriculture, and beyond.

References

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Britannica, The Editors of Encyclopaedia. “bacteriophage”. Encyclopedia Britannica, 2 Feb. 2023, https://www.britannica.com/science/bacteriophage. Accessed 18 July 2023.

D’Herelle, Felix. “Sur un microbe invisible antagoniste des bacilles dysentériques.” Comptes rendus de l’Académie des Sciences 165.

Eaton, Monroe D. and Stanhope Bayne-Jones. “Bacteriophage Therapy: Review of the Principles and Results of the Use of Bacteriophage in the Treatment of Infections.” Journal of the American Medical Association 103, no. 23: 1769–76.

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Global bacteriophages therapy market — industry trends and forecast to 2029. Bacteriophages Therapy Market Growth, Analysis, Size, Share, Forecast, Scope by 2029. (2022, May). https://www.databridgemarketresearch.com/reports/global-bacteriophages-therapy-market#:~:text=Data%20Bridge%20Market%20Research%20analyses,period%20of%202022%20to%202029.