Phage Therapy Re-emerges as an Antibiotic Alternative

Clinicians have used phages to treat bacterial infections since the early 20^th century. Although the advent and mass production of antibiotics caused a decline in phage therapy, the recent rise in antibiotic resistance has renewed the global interest in this line of treatment. In this article, explore the discovery, types, applications, and challenges of phage therapy, along with strategies to overcome its limitations.

Visual representation of bacteria and bacteriophages, highlighting the role of phage therapy in combating infections. — Phage therapy has the potential to treat patients who have severe infections caused by multidrug-resistant bacteria.
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What Is Phage Therapy?

Phage therapy is a lifesaving intervention that uses viruses to treat bacterial infections.¹ Phages, also known as bacteriophages, are viruses comprised of genomic material surrounded by a protein capsid. They infect specific bacteria and use host machinery to replicate via lytic or lysogenic cycles.² For therapeutic purposes, scientists typically prefer lytic (virulent) phages over lysogenic (temperate) phages because the former has a more immediate impact, causing bacterial cells to burst and die.³

Lytic phages including T4 and T7 express proteins such as lysins that cause hydrolysis of a host cell’s peptidoglycan layer, leading to bacterial cell death.⁴ In contrast to lytic phages, lysogenic phages, such as lambda and P22, integrate their genetic material into the bacterial genome and rarely kill the host cells immediately.⁵ However, these phages may eventually cause cellular lysis.

Phages infect specific bacteria with their genetic material and use host machinery to replicate immediately via lytic cycles or latently via lysogenic cycles that follow integration into the host’s genome. After replication, phages assemble within the host and lyse the cell, releasing the phages and killing the host bacterium. Phage therapy makes use of these properties for medical, food safety, veterinary, environmental, and agricultural applications. — Phage therapy helps combat the antibiotic resistance crisis by allowing scientists to target specific bacteria with bacteriophages that infect and destroy host cells without harming beneficial bacterial species.
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Bacteriophage Infection

Each phage possesses specific features that influence bacterial infection. For clinical applications, researchers mostly use bacteriophages belonging to the order Caudovirales, also known as tailed phages. These phages contain receptor binding proteins in their tail fibers, which recognize and bind to specific host receptors present on bacterial cell walls, appendages (e.g., pili and flagella), or polysaccharide capsules.

After binding the bacterial receptor, the phage undergoes a conformational change through complex mechanisms that ultimately open a channel between the phage and host, allowing the phage’s genomic materials to enter the bacterial cell. Thereafter, the phage utilizes the host's machinery to synthesize multiple copies of itself. If the infecting phage is virulent, the infection follows a lytic cycle, or for temperate phages, a lysogenic cycle occurs.

Rise, Fall, and Resurgence of Phage Therapy

Microbiologist Félix Hubert d'Herelle first reported bacteriophages in 1917 and described them as obligate intracellular parasites of bacteria.⁶ He proposed the use of phages as prophylactic and therapeutic agents against various bacterial infections because of their unique antibacterial properties.⁷

Because of d’Herelle’s research, clinicians in the US began using bacteriophages therapeutically around 1922; however, the subsequent discovery of antibiotics, their quick production, long shelf-life, high efficacy against wide ranging pathogens, and widespread usage during World War II led to a decline in phage therapy.⁸ Compared to antibiotics, early phage therapies were difficult to purify and store, and yielded inconsistent efficacy.⁹

Over the years, antibiotics have been misused worldwide, including by physicians prescribing them for viral infections and through their excessive use in animal husbandry and agriculture for disease prevention and enhanced plant growth. This overuse or misuse had led to a rise in antibiotic resistance, which currently poses a major threat to global health. This increase revived phage therapy in the early 2000s.¹⁰

Phage Therapy Approaches

Scientists have developed non-personalized and personalized phage therapy approaches.¹⁰ Non-personalized phage therapy is a one-size-fits-all pre-defined formulation that consists of several bacteriophage strains, while personalized phage therapy comprises active phages that are specifically selected from a pre-existing phage library according to a specific patient’s need.

In comparison to broad-spectrum antibiotics, viruses used for personalized phage therapy infect only targeted pathogenic bacteria without harming beneficial species, which reduces the risk of phage resistence.¹⁰

Depending on the mode of therapeutic action, scientists have categorized phage therapy into five types: conventional therapy, modified phage therapy, therapy with enzymes derived from phages, therapy with proteins derived from phages, and combination therapy.¹²Clinical trials have revealed that personalized phage therapy in combination with antibiotics exhibits superior clinical improvement in patients with a bacterial infection.¹¹

Table 1: Different phage therapy types for bacterial infection treatment¹²

Therapy	Phage types	Mode of actions	Target pathogens
Conventional phage therapy (e.g., monophage therapy and pyophage therapy)	Naturally occurring virulent phages	Lytic cycle	Monophage therapy is effective against vancomycin-resistant Enterococcus faecium septicemia Pyophage cocktail, containing three lytic phages, is effective against burn-causing bacterial species including Pseudomonas aeruginosa and Staphylococcus aureus
Modified phage therapy	Genetically engineered lysis-deficient phages	Enzymatic action Phages deliver photosensitizers or lethal genes encoding holins or restriction endonuclease enzymes to promote programmed cell death (PCD)	Bioengineered E. coli phage T7 produces enzyme disperin B that degrades bacterial biofilms Photosensitizers that release reactive oxygen species (ROS) eliminate methicillin-resistant Staphylococcus aureus (MRSA) strains
Therapy with enzymes derived from phages	Phage enzymes specific for Gram positive bacteria (e.g., endolysins)	Enzymatic action cleaves the covalent bonds in peptidoglycan, damaging the bacterial cell wall and leading to cell death	Endolysins are effective against E. faecalis and E. faecium PlySs2 is an endolysin derived from Streptococcus-infecting phages, which is highly effective against MRSA, Streptococcus pyogenes, S. pneumonia, and S. sanguinis
Therapy with proteins derived from phages	Phage proteins specific for Gram negative bacteria (e.g., virion-associated peptidoglycan hydrolases (VAPGHs) and enzyme depolymerases)	VAPGHs and depolymerases cause bacterial cell wall degradation that enables therapeutic permeability and host cell lysis	Polysaccharide-degrading action allows antibiotics to penetrate and eliminate biofilms formed by Klebsiella pneumoniae
Combination therapy	Antibiotics (e.g., chloramphenicol) can be linked to the phage protein coat by an aminoglycoside bond	Phage-antibiotic synergy (PAS) increases antibacterial effects and minimizes the risk of resistance development by combining multiple antibacterial mechanisms simultaneously	PAS involving β lactams, quinolones, or mitomycin C antibiotics is effective against E. coli

Phage Therapy Applications

Phage therapy is a promising candidate for combating the antibiotic resistance crisis because of its capacity to target and infect specific bacteria. Another advantage of using phages to alleviate bacterial infection is their ability to self-amplify, which potentially reduces the need for repeated dosing.¹³

Besides tackling antibacterial resistance, scientists use phages to combat other problems including the following.

Medical: Phage therapy can treat chronic diseases where bacteria contribute to pathogenesis. For example, scientists have identified a prophage active against Helicobacter pyroli, indicating the possibility of a new phage therapy strategy that could target the etiological role of this pathogen in gastric cancer and gastric ulcers.¹⁴ Clinicians also use phages as prophylaxis to prevent infection among individuals who were in close contact with patients infected with highly transmissible bacterial pathogens such as Vibrio cholerae.¹⁵
Veterinary: At the beginning of the 21st century, phages were orally introduced to reduce Salmonella colonization in broiler chickens.¹⁶ Phage therapy can effectively alleviate mastitis in bovines caused by several bacterial species including those from the Streptococcus and Staphylococcus genera.¹⁷
Agriculture: Phage cocktail treatment prevents Pierce’s disease in grapevines, caused by Xylella fastidiosa subsp. fastidiosa.¹⁸
Food safety: Scientists are currently assessing the efficacy of phages as food product decontaminants, for example, to decontaminate meat from Campylobacter jejuni.¹⁹
Environment: Researchers are investigating applications for bacteriophages as biocontrol agents in wastewater treatment.²⁰

Challenges and Future Considerations

Although phage treatment exhibits significant benefits, it is not easy to formulate phage cocktails with broad-ranging efficacy similar to antibiotics. Bacteriophages are highly specific and act only on certain bacterial genera. Sometimes they even fail to target all pathogenic strains within a bacterial species.²¹ In most clinical cases, patients may contract a variety of pathogenic bacteria, which may limit the desired therapeutic effect of phage treatment.

Personalized phage therapy may require specific phages that are not universally accessible across phage therapy centers. Therefore, scientists often face difficulty in formulating personalized phage therapy because of logistic limitations, and patients may need to be transferred to specific centers for treatment. To overcome logistical challenges, scientists have begun developing point-of-care phage production opportunities using synthetic genomic methodologies to create phage-sized genomes in a permissive bacterial host or via cell-free transcription-translation (TXTL) systems.²²

There are no standard protocols for phage isolation, purification, or clinical use, which leads to variable therapeutic efficacy.²³ The absence of standard protocols for developing phage cocktails also hinders scientists from comparing different phage treatments and their outcomes.

Various strategies, including the creation of Phagistry, an international registry that systematically collects data related to diagnosis, phages, treatments, and outcomes for patients receiving phage therapy, have significantly contributed to enhanced phage therapy development. Furthermore, the effective collaboration of multiple stakeholders including researchers, clinicians, investors, and regulatory bodies will increase phage therapy's applicability.²²

References