Jun Kim Ph.D.

Phages, or bacteriophages, are viruses that infect bacteria. Given their antimicrobial properties they can function as therapeutic agents. Despite successful results in Eastern European countries, the idea of using viruses has not been well received in the West. Also, lack of regulatory framework, the demand for large scale in vivo trials, and difficulty in obtaining intellectual property rights prevent investments from large pharmaceutical companies. Recently, the rise of multi-drug resistant bacteria renewed interest in phage therapy.

The main advantage of using phages as antimicrobial agents is their high specificity for their target bacterial strains[1]. This reduces the potential side effects of damaging commensal bacteria. However, because it is so specific the approach requires careful identification of the target pathogen. Another benefit is that the propagation of phages depends on their bacterial host, making them replicate only at the site of infection by the targeted bacteria. Therefore, phages are self-limiting and self-dosing and do not persist when their specific bacterial pathogen becomes absent[2]. This property is particularly attractive for targeting bacterial biofilms as they are difficult to penetrate.

As with antibiotics, bacteria may evolve to become resistant to phage therapy. Multiple mechanisms have been suggested for development of resistance such as decreasing molecules on bacterial surface that allows the phages to bind or degrading the injected phage DNA[3]. But in response to such resistance phages also co-evolved to overcome these mechanisms. Furthermore, it has been shown that treatment with a range of phages with different modes of infection can make it especially challenging for bacteria to evolve to develop resistance[4].

Despite the benefits, there are concerns that are specific for phages. Phages may carry genes for antibiotic resistance of virulence, which can be transferred to the target bacteria[5]. Also, for the phages that lyse bacteria (lytic phages), a sudden increase in released bacterial molecules as they lyse may induce inflammation and other side effects[6]. Phages themselves can cause immunogenicity from the human host, which can decrease the therapeutic efficacy[7]. There are also manufacturing challenges as the production of phages for certain bacterial species are shown to be difficult.

Phage therapy is a very promising approach. They have been shown to be specific, effective, and generally safe. However, most of the studies that are available do not meet the current standard of clinical trials. Advances in sequencing technologies and other molecular tools are allowing more rigorous characterization of phages, which may facilitate their application as therapeutic agents. Engineered phages have been suggested as an alternative approach for enhanced efficacy while protecting intellectual properties to attract investments from pharmaceutical industry[8]. Given their advantages over antibiotics it would be exciting to see further progress in phage therapy.

References:

1. Koskella B, Meaden S: Understanding bacteriophage specificity in natural microbial communities. Viruses 2013, 5:806–823.

2. Jassim SA, Limoges RG: Natural solution to antibiotic resistance: bacteriophages ‘The Living Drugs’. World J Microbiol Biotechnol 2014, 30:2153–2170.

3. Labrie SJ, Samson JE, Moineau S: Bacteriophage resistance mechanisms. Nat Rev Microbiol 2010, 8:317–327.

4. Nale JY, Spencer J, Hargreaves KR, Buckley AM, Trzepinski P, Douce GR, Clokie MR: Bacteriophage Combinations Significantly Reduce Clostridium difficile Growth In Vitro and Proliferation In Vivo. Antimicrob Agents Chemother 2016, 60:968–981.

5. Balcazar JL: Bacteriophages as Vehicles for Antibiotic Resistance Genes in the Environment. Plos Pathogens 2014, 10.

6. Nau R, Eiffert H: Modulation of release of proinflammatory bacterial compounds by antibacterials: Potential impact on course of inflammation and outcome in sepsis and meningitis. Clinical Microbiology Reviews 2002, 15:95-+.

7. Kucharewiczkrukowska A, Slopek S: Immunogenic Effect of Bacteriophage in Patients Subjected to Phage Therapy. Archivum Immunologiae Et Therapiae Experimentalis 1987, 35:553–561.

8. Oliveira H, Sillankorva S, Merabishvili M, Kluskens LD, Azeredo J: Unexploited opportunities for phage therapy. Frontiers in Pharmacology 2015, 6.