About a decade before the discovery of penicillin, researchers took great interest in treatments using bacteriophages (ie, phages), with the first phages tested against Shigella dysenteriae in 1919. Phages are bacteria-specific viruses and the most prevalent biologic organism in nature, with integral roles in governing bacteria populations. But, the use of phages has been contentious in light of poor documentation of use and variable clinical success. Some researchers even disputed the existence of phages until they were visualized by electron microscopes in the 1940s. Although experts have historically taken a much greater interest in antibiotics, phages have recently garnered newfound interest due in part to increasing antibiotic drug resistance, as highlighted by the authors of a review published in the World Journal of Gastrointestinal Pharmacology and Therapeutics (WJGPT). “Biotechnological advances have further expanded the repertoire of potential phage therapeutics to include novel strategies using bioengineered phages and purified phage lytic proteins,” the authors wrote. “Current research on the use of phages and their lytic proteins, specifically against multidrug-resistant bacterial infections, suggests phage therapy has the potential to be used as either an alternative or a supplement to antibiotic treatments.” Phages are also being considered for use in the battle against coronavirus. Let’s take a closer look at phages and their potential contributions to modern medicine. Phage specifics Phages are simple microorganisms that consist of either DNA or RNA enclosed in a protein capsid. They are viruses that infect bacteria, binding to specific receptors on the bacterial cell surface. The majority of phages only infect bacteria that harbor specific complementary receptors, some of which are specific to certain strains. Other phages, however, can infect across strains and genera. Phages reproduce either by incorporating into the bacterial genome (ie, lysogenic phages) or by commandeering bacterial machinery to reproduce (ie, lytic phages). Lysogenic phages integrate their genetic material into the bacterial chromosome so that each cell division then propagates more phages. Lytic phages, on the other hand, inject their genetic material into the host cell, which multiplies in the cell until critical mass is reached. Then they burst through the bacterial peptidoglycan wall, releasing the new phages to infect other bacteria. Brief history In 1915, the English microbiologist Frederick Twort observed zones of dead bacteria that he hypothesized were caused by some sort of “ultra-microscopic virus.” Just 2 years later, the French-Canadian microbiologist Felix d’Herelle confirmed that viruses were the source of these lysed bacteria and coined the term “bacteriophage.” In 1919, d’Herelle first used phages to treat four cases of pediatric dysentery at the Hôpital des Enfants-Malades in Paris. Others decried his trials for being poorly controlled and his results were debated. Nevertheless, d’Herelle marshaled on with investigations into the use of phages to combat dysentery, cholera, and the bubonic plague, via the establishment of phage therapy centers and commercial production facilities in Europe and India. In one early experiment, d’Herrelle used phages in a cohort of 73 experimental patients and 118 control patients to treat cholera. The study was performed in Punjab in 1931, and showed a 90% reduction in death in the experimental group. Soon, other stakeholders in Brazil and the United States were commercializing the use of phages to fight Staphylococcus, Streptococcus, Escherichia coli, and other bacterial pathogens. But these treatments yielded mixed success. Early trials of phage therapy were plagued by a poor understanding of phages, rudimentary purification schemes, inadequate storage protocols, contamination, low titers, decreased target specificity for bacterial antigens, and poor delivery. To boot, Western experts took far more interest in the emerging field of antibiotics, thus limiting future research into the topic. Moreover, researchers have only recently discovered that innate immunity clears phages, which diminishes the efficacy of the therapy. Intriguingly, researchers in Eastern Europe and the former Soviet Union have performed clinical trials of phage therapy over the past 100 years, and have used it to treat antibiotic-resistant infectious caused by Salmonella, Enterococcus, Staphylococcus aureus, Streptococcus, Pseudomonas aeruginosa, Proteus, E. coli, and S. dysenteriae, with effective applications in surgical, therapeutic, and prophylactic contexts. Modern phage therapy Phages have enviable therapeutic profiles, according to Peter Marks, MD, PhD, director of the Center for Biologics Evaluation and Research at the FDA. In FDA proceedings from 2017, he explained that “[P]hage therapy appears to be non-toxic in humans and in animals, and phage have the benefit that their bacterial specificity allows sparing of the remainder of the beneficial microbiota. In addition, there's the potential to either select or engineer phage to target bacteria that develop resistance to these agents.” The authors of the aforementioned review article in WJGPT pointed out that lytic phages are a better therapeutic choice compared with lysogenic phages. They also hypothesized that phages may make good adjunct therapy. “Phage lysins may thus be a much more practical therapeutic tool for their decreased immunological potential, among other reasons such as ease of production, purification, and storage,” they concluded. “Despite the promising preliminary findings on phage and phage-derived lytic proteins, it is more than likely that no panacea for antibiotic-resistant infections will arise,” they added. “The increased efficacy of antibacterial agents when used in conjunction implies that therapy using some combination of phage, phage-derived lytic proteins, bioengineered phage, and/or antibiotics will be necessary for addressing the growing problem of antibiotic-resistant infections.” In 2018, encouraged by a series of high-profile cases of phage therapy involving intractable infection, the University of California San Diego launched the Center for Innovative Phage Applications and Therapeutics (IPATH). Their first clinical trial was greenlighted by the FDA in 2019, marking the first time an intravenous phage therapy was given the go-ahead by the agency. The phase I/II clinical trial involves an experimental bacteriophage combination to treat patients with ventricular assist devices (VADs) infected with S. aureus. “There is a high, unmet need in patients with S. aureus VAD infections, which are typically very difficult to eradicate with conventional antibiotic therapy,” said Saima Aslam, MD, principal investigator and medical director of the Solid Organ Transplant Infectious Disease Service at UC San Diego Health. Recent research has shed light on the use of phages to battle viruses—including COVID-19—and fungal infections. Phages could be used as adjunctive antiviral therapy, based on research published in the journal Future Microbiology. They could also be used to fight comorbid bacterial infections that affect more than 40% of those with COVID-19. “Phages may protect eukaryotic cells by competing with viral adsorption and viral penetration of cells, virus-mediated cell apoptosis as well as viral replication,” the authors wrote. “Phages may also induce antiviral immunity while contributing to maintaining a balanced immune response. Moreover, by inhibiting activation of NF-κB and ROS production, phages can downregulate excessive inflammatory reactions relevant in pathology and clinical course of COVID-19.” Source
