Updated: Jan 23
Antibiotics are one of the greatest scientific advances ever made. A world in which a simple bacteria infection would end up in death is now foreign to many of us due to the prevalence of antibiotics. However, the rise of antibiotic resistant bacteria has sparked fear that such a world will become reality again. Groups such as the World Health Organization have deemed antibiotic resistant bacteria a critical threat, estimating that by 2050 there will be no effective antibiotic available to treat infections if no new drugs are developed . Due to the slowing pace of antibiotic development and the rapid rise of antibiotic resistance, new treatment methods are being investigated by researchers . One particular treatment that has perhaps been the most talked about is phage therapy.
Phage therapy is the method of using bacteriophages, viruses that specifically infect bacteria, to treat bacterial infections .Their ability to infect bacteria was first observed by French scientist Félix d'Hérelle . This started an initial effort of scientists to isolate bacteriophages to use against bacterial infections. However, the prevalence of antibiotics caused phage therapy to come to a standstill . In recent decades, interest in phage therapy has been renewed as it possesses several properties that make it optimal to deal with antibiotic resistant bacteria. For one, phages infect bacteria through mechanisms that are different from how antibiotics work. As such, numerous studies have shown the ability of phages to inhibit multi-drug resistant (MDR) bacteria . In one study, researchers were able to cure mice infected with MDR Staphylococcus aureus with the bacteriophage phage phi MR11 . Similar success has been demonstrated with human patients such as the successful treatment of diabetic toe ulcers with anti staphylococcal bacteriophage Sb-1 . Second, bacteriophages have been demonstrated to have little side effects . Bacteriophages have high host specificity. Hence, they do not infect other cells in the organism . Their only side effect is a possible immune response from both the humoral and cellular immune systems with less than severe symptoms typically. It has been hypothesized that the rapid release of bacteriophage antibodies in certain cases may lead to dangerous immune reactions such as anaphylaxis, but that has not been reported in cases of phage therapy . Third, bacteriophages are vastly abundant, being perhaps the most abundant life forms on earth, and are constantly replicating and evolving. They are ubiquitous organisms found in many diverse environments such as soil, water, feces, etc . Hence, it is unlikely that we would run out of bacteriophages .
For all the research there is in phage therapy, one may well wonder why hospitals are not using phage therapy currently. This is because there are issues to phage therapy preventing it from being used widespread. One such issue is that bacteria have developed defense mechanisms against bacteriophage infection through a variety of mechanisms including CRISPRs, restriction modification systems, and more . Additionally, due to the specific host range of bacteriophages, a bacterial infection has to be analyzed and then the right bacteriophage strains selected for phage therapy, a costly effort . Another issue is that the pharmacokinetics, the study of a drug's path through an organism’s body, of phage therapy is quite complicated and not well-defined .
Each of these issues had prevented phage therapy from becoming a reality, but now new developments in phage therapy have helped pave a path through these issues. In dealing with bacteriophage resistance, it should be noted that it is highly unlikely that there will evolve a bacteria resistant to all bacteriophages. However, as bacteriophage resistance is a concern, multiple different strategies have been proposed to deal with bacteriophage resistance such as the anti-virulence strategy, a strategy that uses a bacteriophage as a selective pressure to shift the bacterial population to one that carries fewer infectious factors, and the antibiotic-phage combination therapy, which mixeds phages and antibiotics into a cocktail [2, 12-16].
In past decades, selecting the appropriate bacteriophages from bacterial infection analysis was difficult due to technological limitations. However, modern technological capabilities make the isolation and identification of bacteriophage strains relatively straightforward. The only issue is to assemble a database of various bacteriophage strains, a process that has already begun . Finally, many recent new studies into the pharmacokinetics of phage therapy have revealed important details on the dosages needed for effective treatment and new methods that can improve the pharmacokinetics of phage therapy such as nanoparticle encapsulation [21, 22].
Bacteriophage therapy has potential to save lives and deal with the antibiotic resistance bacteria problem. Its ability to attack antibiotic resistance bacteria, its few side effects, and its abundant supply has given it much attention. Although several obstacles such as phage resistance have prevented it from being applied, advances and strategies to overcome these obstacles have been made. Currently, there are several FDA clinical trials utilizing phage therapy. These include Adaptive Phage Therapeutics’ bacteriophage therapy for prosthetic joint infections, and Yale’s cystic fibrosis bacteriophage therapy . In addition, numerous biotechnology companies have invested into phage therapy, and it is expected that the phage therapy market will hit its peak between 2021 and 2028 . For those who desire to help partake in the battle against antibiotic resistant bacteria here at Cornell, one should look no further than Cornell's own Professor Josh Chappie, whose work has been to understand bacteria defense mechanisms against bacteriophages .
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A first step toward liposome-mediated intracellular bacteriophage therapy
Biotechnological applications of bacteriophages: state of the art
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