Suffering from Success: Our Ongoing Battle Against Bacteria, and How We Gain the Upper Hand

    A tempting solution to this seemingly catastrophic problem is to just pump more money into looking for more antibiotics that bacteria aren’t resistant to yet, and this would make sense initially. However, new antibiotic development has slowed in recent years¹⁵, and the endless march of evolution is likely to result in the same problems as before. Perhaps, then, the best option is to find a treatment that can evolve alongside bacteria. In this case, the way forwards takes us to a lesser-known solution from the past.

    In 1917, the microbiologist Félix d’Herelle described “an invisible microbe” that could kill bacteria with much greater efficacy than any other methods known at the time. This was the bacteriophage, discovered by William Twort two years earlier (where Twort had not realized their antibacterial potential as d’Herelle did). Different bacteriophages, or phages, were seen to target specific bacterial species and strains, highlighting their vast medical potential¹⁶. This was a leap towards controlling bacterial infections that would previously have been fatal, and there was much international success in so-called “Phage therapy”, both disease-preventing and disease-curing, in the following 1920s and 1930s. The dawn of the age of antibiotics in the 1940s, however, soon relegated this innovative use of bacteria’s natural enemy to the past – at least in the West. To this day, phage therapy is being developed and used in Eastern Europe (with plausibility in the idea that Soviet development of phage therapy “tainted” the field, and dissuaded Western scientists from further contribution¹⁷). Is it time for researchers across the world to return to our neglected friend, the bacteriophage?

    There seem to be a lot of benefits to this, at least with lytic phages (as these replicate in the bacteria until the host cell bursts or “lyses”, whereas lysogenic phages incorporate their DNA into the host genome and allow the bacteria to pass on the DNA to future generations, potentially spreading antibiotic resistance genes as mentioned before). Phages can eliminate bacterial infections without affecting human cells, and their levels increase over the course of treatment while antibiotic levels only decrease over the course of treatment. Additionally, they can be produced very easily at low cost, and there are many different phages that are specific to strains of bacterial species^18,19. Phage specificity is a huge advantage to this therapy, as it means there is less need for broad-spectrum antibiotic use which can kill other, non-harmful bacteria in the gut and disrupt the gut microbiome. As phages still have the capacity to evolve, and co-evolve with their bacterial host²⁰, there may be some changes to their efficacy as treatment. This, however, can be countered by the use of phage “cocktails”, where several different phages all specific to the same bacterial species are administered²¹. Furthermore, phage “training” is a novel concept also used to ensure phages can beat the bacteria. This involves leaving bacteria and phage together for extended periods of time, allowing them to co-evolve in a biological “arms race” that increases phage infectivity and host ranges (how many strains of a bacterial species they can infect), and reduces bacterial resistance of the original “ancestral” bacterial generation to this trained generation of phage²². This method used by Borin et al²³ found promising results in their initial report in training phages against E. coli, and there’s potential for its use in developments of phage therapies.

    For administration of phage therapy, there are many options. Historically administration of phage went through any of the following routes: topical, intramuscular, subcutaneous or intraperitoneal. But, in recent times researchers have found encapsulating phages in materials like alginate (a polymer derived from brown seaweed) to be an effective way to prepare phages to survive gastrointestinal conditions, like high acidity, for oral delivery into the gut²⁴, meaning many gut-based infections could potentially be ameliorated. Even more interestingly, one team of researchers genetically engineered an E. coli-specific phage to express an E. coli outer membrane protein, allowing it to survive the gastrointestinal tract’s extreme acidity²⁵. Further “designer phage” work includes modification of phage receptor binding proteins (proteins that allow phages to attach to bacteria), with this modification increasing phage host ranges²⁶. Some animal trials of phage therapy have already happened with some success, including phage use against V. cholerae (the bacteria that causes cholera) in rabbits²⁷. Clinical trials involving humans are ongoing, primarily in France and the United States, and mainly focus on E. coli, S. aureus, K. pneumonia, and P. aeruginosa²⁸. Before phage-only therapies are much more widely available, success has been found in combining antibiotic and phage therapies against antibiotic-resistant bacteria. Bacteria maintaining resistance to both phage and antibiotics can often be costly to its resources, and so this combination therapy results in bacterial susceptibility to either treatment, a phenomenon known as Phage-Antibiotic Synergy (PAS)²⁹.

    There are current limitations to how far phage therapy can be adopted while still adhering to modern manufacturing standards, known as Good Manufacturing Practice (GMP)³⁰. As phages are biological products capable of evolution, and phage treatments (including cocktails and trained phages) may be tailored to resolve specific bacterial infections of a single patient, following these high GMP standards for constantly updated bacteriophage treatments may be extremely time-consuming and costly³¹. Also, natural bacteriophages can be difficult to patent unless they are obviously genetically modified or are used in combination with other engineered phages^31,32, as natural phages are not a novel invention. This may pose a problem for investment from pharmaceutical companies, as a lack of patentability of a treatment can disincentivize investment into its manufacturing. These concerns are yet to be resolved, although flexible medical licensing with regards to phage therapies would be helpful in getting specialized or personalized phage treatments into use quicker.

    Recent developments in bacteriophage therapy all suggest seemingly limitless potential for its wider use in tackling our growing problem of antibiotic resistance. With more and more attention being focused on the once overlooked phage solution, we may be able to see a new “golden era” for phage therapies, similar to that celebrated by antibiotics in the previous decade, and overcome a pressing issue threatening modern medicine as we know it.