Treatment of bacterial infections with bacteriophages (phages)—viruses that enter bacterial cells and rapidly multiply, quickly rupturing the cells and destroying the bacteria—has been known to be effective since the early 1920s. The advent of broad-spectrum antibiotics led to a halt in phage therapy research, however, except in Eastern Europe, particularly Georgia, and to some extent France (1).
Bacteria, meanwhile, have developed resistance to many antibiotics, and new “superbugs” that cannot be treated with even the most powerful antibiotics are increasingly common. There is real potential that the world could enter a post-antibiotic era in which giving birth or getting a simple
cut could present a serious risk of death. The situation is exacerbated by the fact that antibiotics have long since been commoditized, and most major pharmaceutical companies halted their antibiotic development programs in favor of investments in more lucrative areas such as oncology. Few new antibiotics drugs have been approved as a result.
Consequently, the need for alternatives to traditional antibiotics has become urgent. In addition to leading to the development of novel chemical approaches, the current threat of antimicrobial resistance is driving renewed interest in phage therapy. A lack of appropriate infrastructure and specific regulatory framework are two main challenges to the realization of marketed products. Fortunately, developers of phage-based treatments expect these hurdles to be surmountable in the medium term, with several candidates in or soon to enter clinical trials.
Drug resistance not the only driver
Fighting bacteria that are resistant to current antibiotics is what most people see as the main driver of interest in the development of phage-based therapies. For Alexander “Sandro” Sulakvelidze, president and CEO of bacteriophage developer Intralytix, there is another important factor: growing understanding of the human microbiome and its role in health and disease.
“The microbiome field is exploding, with a lot of bright minds working in the area. People are establishing links between microbiome composition and diseases ranging from those having obvious bacterial etiology (e.g., infectious and gastrointestinal diseases like bacterial dysentery) to disorders that are not typically associated with bacterial infections, such as obesity, cancer, and others,” Sulakvelidze explains. “That means that with bacteriophages we not only have the potential to manage drug-resistant infections, but also a tool that may be able to beneficially modulate the microbiome to address both infectious and noninfectious diseases,” he states.
Indeed, the human microbiome comprises hundreds of bacterial species, and maintaining the right balance of “good” and “bad” bacteria in the gut microbiome helps maintain health through multiple mechanisms including modulation of inflammation and regulation of protective gastrointestinal functions, according to Sulakvelidze. “Lytic bacteriophages are superbly suited for gentle and targeted fine-tuning of the microbiome by killing their specific targeted bacterial pathogens without disturbing the normal microflora—a unique biological property that is increasingly explored for developing novel tools for microbiome modulation and research,” he observes.
Different mechanism of action
While broad-spectrum antibiotics are attractive because they can be used to treat a wide range of bacterial infections, they also do not discriminate between “good” and “bad” bacteria. Dysbiosis and secondary infections (e.g., fungal infections, inflammatory bowel disease, reactive arthritis, etc.) can occur as a result, complications that have not been observed with phages (1). Phages could also be beneficial for patients with allergies to the commonly used penicillins, sulfonamides, and tetracyclines.
At the simplistic level, notes Sulakvelidze, phages infect bacteria by first attaching to their cell membranes. They then inject DNA into the host cells. Within 60 seconds, the phage DNA takes over and shuts down the cellular machinery of the bacteria, which allows for phage DNA replication. Within 20–40 minutes, approximately 40–200 bacteriophages exist in each of the bacterial cells, causing the cells to burst. The bacteria die, and the phages are released to seek out and infect additional targets.
This mechanism of action is different from that of traditional antibiotics. As a result, while bacteria can become resistant to phages, the mechanisms involved are very different from the one against antibiotics. “The resistance that bacteria develop to antibiotics does not affect their resistance to phages, making these two approaches complementary,” Sulakvelidze observes. Indeed, often phages can be effective against bacteria that have developed resistance to antibiotics. There have been several case reports of the effective emergency treatment of patients for which conventional antibiotics have failed (1).
Specificity a two-edged sword
The specificity of phages is advantageous because it does not result in the death of desirable bacteria. It is, however, one of the reasons that phages fell out of favor after the introduction of antibiotics. For phage therapy to be effective, it is necessary to know which bacterium is causing the infection, which is not the case for broad-spectrum antibiotics, according to Sulakvelidze. It can take time to identify the specific phage or cocktail of phages that will be effective, time that some patients may not have, particularly in cases where phages are used as a treatment of last resort (1).
Antibiotics creating problem and inhibiting alternative solutions
Another difficulty facing the advance of phage-based therapies is the fact that the medical infrastructure that exists for the treatment of bacterial infections in most of the world has been designed around antibiotics (2). From susceptibility testing kits to the sophisticated machinery required for high-throughput testing and the training of hospital and clinical personnel, everything is geared toward antibiotics, Sulakvelidze comments.
“The business model for phages is very different from that for antibiotics, which creates a whole range of challenges from manufacturing and distribution to diagnosis and identification of the right phage treatment for each patient,” says Sulakvelidze.
For Grégory Resch, head of the laboratory of bacteriophages at the Center for Research and Innovation in Clinical Pharmaceutical Sciences at Lausanne University Hospital, Switzerland, one of the biggest challenges is the complexity around producing many different specific phages under good manufacturing practice (GMP) conditions, which contrasts with the existing access to broad-spectrum antibiotics. He also notes that patenting phages is not as obvious, because many of them can easily be isolated from the environment.
Phages are manufactured via fermentation using the bacteria that serve as the natural host of the phage in question. The phage reproduces, killing the bacteria. The phage must then be separated from the dead bacteria and purified, as the dead bacteria and other contaminants can cause undesired immune responses. Fortunately, advances in fermentation technology and downstream processing have enabled successful, large-scale production of high-quality phage-based products, according to Sulakvelidze.
Production challenges, although they are being addressed, are further complicated by a lack of an established regulatory framework for the approval of phage-based therapies. The absence of a clear definition for bacteriophages, common and validated dosage protocols, and the length of phage treatments, for instance, creates uncertainty with respect to the development of clinical programs (2). On the positive side, however, many of the disadvantages of phage-based therapy relate to infrastructure and knowledge gaps that can be resolved as the field progresses.