Author: Celine Tedja
Editor: Altay Shaw
In modern times, antimicrobial resistance (AMR) has become a major global health threat, as declared by the WHO. Microbes, like bacteria, develop AMR when they lose their susceptibility to certain drugs or treatments intended to work against them. These days, the extensive use of antibiotics to treat bacterial infections has led to an increasing prevalence of resistant bacterial strains. Antibiotics may eventually lose their effectiveness against certain bacteria, a serious issue that often goes unnoticed. Furthermore, developing novel antibiotics is highly challenging, costly, and time-consuming. If the currently available antibiotics fail to treat a bacterial infection as a consequence of antimicrobial resistance, a person’s life may be at risk. Globally, bacterial AMR was directly attributed to 1.27 million deaths in 2019.
With growing concern towards the emergence of antibiotic-resistant bacteria, researchers have tried to find viable alternatives to antibiotics. One way that has sparked interest is using naturally occurring bacteriophages as antimicrobial agents. Bacteriophages (often shortened as ‘phages’) are viruses that specifically target bacteria. They are bactericidal (capable of killing bacteria) and are specific to particular bacterial strains, thus having the potential to be used for treatment.
Bacteriophages are abundant and ubiquitous entities, with an estimated total of 1031-1032 existing in the world at any given time. They play a crucial role in controlling bacterial populations and maintaining a microbial balance. As viruses, phages are non-living and dependent on a host (in this case, bacteria) for reproduction. Phages are composed of DNA or RNA encapsulated within a protein capsid. Lytic phages disrupt bacteria through several steps. Firstly, they bind to specific receptors on the bacterial (host) cell surface, before injecting their genetic material (DNA/RNA) into the host cell. The genetic material then hijacks the host cell’s machinery, resulting in the synthesis of new phage DNA/RNA and proteins. These newly synthesised components are then assembled into intact phages. Eventually, the host cell reaches a point when it lyses, releasing the newly formed phages that can reinitiate the cycle.
Bacteriophages offer several advantages over antibiotics in treatments. First and foremost, unlike antibiotics, phages are specific to a targeted bacterial species, hence reducing the risk of microbial imbalance in the human body due to the disruption of microbial flora. Another point is the self-replicating ability of phages at the site of infection, meaning that they can theoretically achieve efficacy after a single dose. Meanwhile, for antibiotics, multiple doses are required to maintain concentrations and availability at the site of infection. In addition, bacteriophages are found to be capable of penetrating biofilms (i.e., a community of microbes that sticks to a surface by a polymeric matrix) due to the presence of enzymes capable of degrading biofilms. So far, fewer side effects have also been reported for bacteriophages.
Despite the potential benefits, bacteriophages have several limitations to antibiotics. The highly specific nature of phages can be disadvantageous when intending to treat multiple bacterial species. In this case, a phage cocktail, i.e., a mixture of different phages aimed at broadening the host range, can be used. However, designing a phage cocktail with the correct composition is more challenging than designing an antibiotic combination, due to the huge diversity of available phages. Besides, we currently still have a limited understanding of the safety profile and exact modes of action of different phages. There are also no clearly defined protocols for the administration of phages.
Interestingly, the therapeutic use of phages is not a recent discovery. The history of phage therapy, in fact, dates back over a century. Frederick Twort, a British bacteriologist, was the first to discover the bacterial lysis phenomenon associated with bacteriophage in 1915. However, it was the French-Canadian microbiologist Félix d’Hérelle who coined the term ‘bacteriophage’ and conducted the first therapeutic application of bacteriophage in 1919. He used phages to treat 4 cases of dysentery at a hospital in Paris, and the trial was proven successful. Despite some disputes, he continued his research on phage therapy. In the 1940s, phage therapy was widely used in the former Soviet Union and Eastern Europe to treat a range of infections, such as typhoid fever and cholera. In contrast to this, the Western world mostly remained skeptical towards phage therapy due to its lack of reliability (e.g., improper purification and storage in early trials). Moreover, the market success of the antibiotic penicillin at that time, which was perceived as more potent, further diverted people’s attention from phages.
However, the escalating threat of antimicrobial resistance has revived interest in phage therapy among many scientific communities worldwide. Several institutions have invested in researching bacteriophages and conducting clinical trials. For example, in 2016, researchers from the Centre for Phage Technology at Texas A&M University and the US Naval Medical Research Center successfully treated a case of multidrug-resistant (MDR) Acinetobacter baumannii using intravenous phage cocktails. In the same year, researchers from Yale University successfully used a mixture of phage called OMKO1 and the antibiotic ceftazidime to treat a case of MDR Pseudomonas aeruginosa.
Cutting-edge biotechnology nowadays has also led to advancements in phage therapy research, one of which is the isolation of phage-derived lytic enzymes called lysins. Using these enzymes instead of a whole bacteriophage potentially prevents the risk of transfer of resistance genes among bacterial populations via transduction (i.e., through bacteriophages). Besides, lysins would be easier to administer than phages, since lysins would not induce an immune response in the human body, unlike phages. Another point is the relative ease of purification and storage of lysins compared to phages. Therefore, phage-derived lysins are considered a promising subject in the research and development of phage therapy.
Nonetheless, deeper insights into various aspects of phage therapy are still needed before phages or their derivatives can be brought into commercially available pharmaceutical products. In 2021, the National Institute of Health (NIH) granted $2.5 million to 12 institutes around the world to support research on phage therapy. More clinical trials on phage therapy and genetic engineering to improve efficacy are coming. Should regulatory agencies confirm their overall high efficacy and grant approval, phages could serve as an ideal substitute for antibiotics, effectively addressing the growing issue of antimicrobial resistance.
kinesismagazine.com 