A Path to Fighting Bacteria in the Post-Antibiotic Era
The COVID-19 pandemic has changed our lives in ways we never could have imagined. We have witnessed it cause over two million deaths worldwide, crippling our economies and exposing various systemic health inequities. But as challenging as this situation may be, it’s simply a mere fraction of the biological threat approaching in the next 30 years. To fully understand this issue, we need to go all the way back to 1928, when the first antibiotic was discovered.
The advent of a post-antibiotic era
Sir Alexander Fleming’s observation that a chemical produced by a fungus so effectively killed bacteria was a discovery of great importance. The antibiotic compound isolated from this fungus, penicillin, provided a simple yet effective treatment against the pathogens that plagued humanity for so long. As synthesized in a report by Adedeji (2016), this marked the beginning of a medical revolution. Bacterial infections, which were responsible for the majority of deaths worldwide, were able to be treated, shifting the leading cause of death to non-transmissible diseases, and helping raise the average life expectancy from 47 to 78.8 years of age. Over time, more and more types of antibiotics were discovered, adding to our arsenal of treatment options to combat pathogenic bacteria (Adedeji, 2016).
In the present day however, the effectiveness of antibiotic treatment is steadily declining, for two reasons. The first is that research into new, stronger classes of these drugs rarely yields effective compounds, creating a lack of incentive to invest in their development. This is why very few viable antibiotics have been discovered since the 1980’s.
The second (and more pressing) reason is the growing concern over the rise in bacteria withstanding antibiotics, effectively making these drugs obsolete for treating infections. This is called antibiotic resistance, and the World Health Organization (2020) predicts that it will skyrocket into one of the largest global health challenges humanity will ever face. This is supported in a report from the United Nations Interagency Coordination Group (IACG), which demands immediate action from multiple industries to combat this escalating healthcare emergency. They state that mainly antibiotic resistance, coupled with broader resistance from other types of microbes, will result in 10 million deaths per year by 2050, and over $100 trillion in economic losses (IACG, 2019; WHO, 2020).
Evidently, this is a dangerous issue. We are headed towards a world that will be rampant with incurable infections — where a single cut could be deadly. So, how did this happen?
Antibiotic resistance has been amplified by agricultural and medical practices
Killing bacteria in agriculture is paramount, since it prevents food shortages from dead crops or livestock and the financial damages that result. A report by ter Kuile and colleagues (2016) states, however, that approximately 50–80% of the antibiotic resistance we see today has been caused by antibiotic misuse in this industry. Generally, these drugs are employed by a variety of commercial farms for use as prophylactics, growth hormones and hygienic agents. However, their dosages are often unregulated, and given in smaller-than-lethal levels. This allows for a portion of the bacteria to survive, and through such selective pressure they propagate resistance genes. These bacteria then proliferate in the animal product, eventually bioamplifying up the food chain into human consumers, or spreading into the environment (ter Kuile et al., 2016). Even the improper use of antibiotics in pharmacy, whether it be prescribing them for viral infections or not completing a full dose, all contributes to antibiotic resistance.
It’s important to keep in mind that bacteria have been around for much longer than humans. Over billions of years, they have experienced ruthless competition against other organisms. Not only have they dealt with the life-killing substances from plants and fungi, but have had to manage their own biocidal chemicals to deter other predators. Julie Perry and colleagues, from the DeGroote School of Medicine at McMaster University, describe how this gradually resulted in the creation of “the antibiotic resistome,” a collection of genes encoding for drug resistance. In hindsight, it comes as little surprise that when faced with massive amounts of antibiotic use, bacteria quickly expressed resistance mechanisms by tapping into this reservoir of genomic material (Perry, Waglechner, & Wright, 2016).
Unfortunately, this issue is incredibly hard to solve. We’re up against a sophisticated domain of life that takes advantage of many aspects of our human activities to spread and take over. Of course, while a problem like this can be overwhelming, a variety of efforts have been undertaken to combat it.
A multifaceted approach to solving antibiotic resistance
To start, there has been extensive research on the exact molecular mechanisms bacteria use to resist antibiotics. A 2014 review by Blair and colleagues describes that, in essence, antibiotics function by binding to a specific part of the bacterial cell (called the target site), causing major damage to it. This damage has widespread negative effects on the overall bacterial metabolism, resulting in the cell’s death. Hence, antibiotic resistance mechanisms involve the protection and modification of these target sites (Blair et al., 2014). Most predominantly, bacteria use structures called efflux pumps to propel antibiotics out of the cell and away from these sites. They also employ the use of other enzymes to change the biology of their target site, or destroy or inactivate the antibiotic itself (Blair et al., 2014).
Understanding the ways in which bacteria survive antibiotic treatment is crucial to developing new drugs to combat antibiotic resistance. This, along with surveillance of the vertical and horizontal transfer of resistance genes to predict outbreaks, to more robust infection prevention and control, represent the set of medical avenues that are being researched to tackle this global health challenge.
But potentially the most exciting development in the fight against antibiotic resistance is the use of treatment methods that are different from antibiotics. And one that shows great promise is phage therapy.
Interestingly enough, this treatment was discovered almost a decade before penicillin, independently by bacteriologists Frederick Twort (in 1915) and Félix d’Hérelle (in 1917). As described by UC San Diego, they both noticed how certain bacterial colonies were being killed by a microscopic predator which they thought to be a tiny virus. D’Hérelle in particular called it the bacteriophage, meaning “bacteria devourer” (however, this virus is often just referred to by its short form “phage”). A few years later, d’Hérelle would go on to use phages in their first successful therapeutic application: treating dysentery (UC San Diego, 2021).
Ever since then, phage therapy had been studied by researchers all over the world. But even with all this investigation, little was known about how exactly these viruses killed bacteria, and how to properly prepare them to use in patients. This led to the publishing of a variety of studies documenting the effects of improperly used phages, painting a negative image of the treatment’s effectiveness. And compared to the simpler and more easily distributable antibiotics which were discovered soon after, phage therapy gradually lost interest in Western medicine. However, research still continued, especially in places where antibiotic availability was limited. While antibiotics were the main treatment throughout North America, phage therapy was used more in the former Soviet Union (UC San Diego, 2021).
Over the decades, phage therapy has been trending in a positive direction. Studies around the globe have uncovered much more of the fascinating nature of these viruses, filling in some of the gaps in knowledge we had previously. And due to the advent of antibiotic resistance, as well as successful modern day uses of phages, this treatment has gained renewed interest in fighting bacteria once again.
Phages are a possible shining ray of hope in the dark fight against resistant bacteria
Currently, phages display high potential as an alternative medicine to antibiotics, mainly because they effectively kill bacteria with antibiotic resistance, and degrade biofilms. Described by Lin and colleagues (2017), they do this by binding to the bacterial cell, inserting their genome into it, hijacking the bacteria’s metabolism, and using it to create new phages called progeny. These progeny then release enzymes that degrade the bacterial cell wall, causing it to effectively “explode” and release up to thousands of new phages into the environment for further bacterial colony infection (Lin et al., 2017).
But the potential of phage therapy isn’t just limited to it being a standalone medicine. As discussed in a review by Kailtyn Kortright and colleagues (2019), phages can be used alongside or even bolster antibiotic treatment. They give the example of a phage binding to an efflux pump. Due to the rapid evolutionary pace of bacterial colonies, many bacteria will remove this efflux pump in future generations to prevent phage binding. However, this also eliminates the main resistance mechanism the bacteria have to antibiotics, making them once again vulnerable to treatment. Hence, in the cases where phages target a resistance mechanism on a bacterial cell, these bacteria likely become resensitized to antibiotics (Kortright et al., 2019).
A real-life example of this phage-antibiotic synergy is described in the case study of Chan et al. (2016), who used a phage to aid in the treatment of an organ surgery infection. In general, organ surgeries carry a high risk of infection due to exposure of protected areas in the human body (Chan et al., 2016). Antibiotics are often used to prevent such infections, but are becoming less and less effective as antibiotic resistance continues to grow. This was the case in the patient discussed in this study, who had a resistant aortic graft infection of the bacteria P. aeruginosa. Years of treatment with the antibiotic ceftazidime could not quell the infection, so Chan and colleagues employed the use of a phage titled OKMO1 for assistance. After some time of treatment, they found that P. aeruginosa was resensitized to ceftazidime, and the infection eventually subsided (Chan et al., 2016).
Phage therapy faces obstacles to being implemented in Western medicine
Findings like those in the case study above illuminate the high potential phage therapy has in saving lives, as well as preventing current treatments like antibiotics from moving into obsolescence. But unfortunately, this is contrasted by the tall regulatory hurdles it faces in Western medicine.
Chan and colleagues (2013) attribute this to the personalized nature of phages. Phages and bacteria have been in a coevolutionary war with each other for billions of years. While bacteria cultivated unique defence systems to prevent infection, phages countered through developing their own sophisticated infection mechanisms. Now in the present day, there are approximately 10^31 phages on earth, each of them having unique modes and ranges of infectivity. Depending on the type of phage, it may only infect a few strains of bacteria, or multiple genera. Additionally, the way these phages go about their infection may not be conducive to the health and safety of the patient in which the target bacteria reside (Chan et al., 2013).
So to use phages in therapy, a specific, suitable phage or group of phages needs to be chosen and properly analyzed to safely clear the bacterial infection (a process called characterization). Researchers use a variety of methods solely for figuring this out — however, because of phages’ incredible diversity, no single, streamlined process is used to complete this task (Chan et al., 2013).
With such variation in how research groups approach phage characterization, phage therapy itself is currently not conducive to Western medicine. The regulatory frameworks that build our medical system call for a single, streamlined product or process that can be replicated for every patient in a clinical trial, while still providing successful treatment. And for good reason: a controlled clinical trial ensures that a drug or remedy works properly, and can be safely used and distributed on a large scale. Unfortunately, since there is no streamlined process for using phages to treat bacterial infections, it cannot pass these trials, creating a lack of certainty as to whether they are actually viable at this large scale (Brüssow, 2012; Chan et al., 2013).
This is inherently one of the downfalls of such a personalized medicine. While it has the capability to provide the best possible treatment for an individual, it requires too many resources to be scaled up for an entire population. To make matters worse, there are other regulatory obstacles phage therapy faces, like difficulty in claiming intellectual property (IP) making it hard to fund.
Reassuringly though, the field of synthetic biology may hold routes to subverting these limitations.
Phage lysins and synthetic phage engineering may overcome Western medicine regulatory hurdles
One such route is the use of phage lysins. Described in an article by Vincent Fischetti, PhD and Head of Laboratory at Rockefeller University, lysins are the enzymes phage progeny release to degrade the peptidoglycan cell wall of bacteria. They are also employed by phages to initially insert their genome into the bacterial cell (Fischetti, 2018).
Lysins, like phages, are specific to certain bacteria, and generally correspond to a phage’s host range. Research into these enzymes, however, has created different variants which can target more bacterial hosts, through modifying or combining them. What’s exciting about using lysins to destroy resistant bacteria is that they mount many of the obstacles phage therapy faces.
Methods developed by the Fischetti Laboratory have allowed for successful, generalized approaches into isolating and purifying a variety of these compounds. Since lysins can be sourced and distributed in this manner, they don’t face the blockades traditional phage therapy has in passing clinical trials or claimig IP. Fischetti (2018) notes that currently, biotech companies like ContraFect are developing and testing lysin-based drugs for patient use (Fischetti, 2018) — marking an exciting step forward in the implementation of this novel therapeutic.
Another route to overcoming phages therapy’s regulatory hurdles through engineering synthetic phages. As explained by Magda Barbu and colleagues (2016), the biology and genome of phages can be altered through synthetic biology techniques so that they exhibit more desirable characteristics. Some examples include designing phages to infect a greater number of resistant bacteria, engineering them to avoid detection from the human immune system, and creating specialized phages that can be produced in more economically efficient ways (Barbu, Cady, & Hubby, 2016).
By literally creating the perfect phage to destroy a single or even multiple infections, synthetic phage engineering presents a promising route for the future of phage therapy.
Moving forward…
The problems we face today are complex. While just comprehending them is one thing, developing a viable solution can be challenging in itself. In outlining the limitations of phage therapy, it seems that a resolution to antibiotic resistance may never come easily. It indeed is a complex issue, affecting not only the medical sector, but having drastic consequences economically, politically and socially.
This makes one thing evident, however. The public, physicians, pharmaceutical companies and policy makers need to unite in a multi-stakeholder effort to prevent the bleak future we are approaching. The diverse and unique perspectives shared among these different disciplines not only creates a full understanding of the issue, but best allows us to craft solutions that address each aspect of the issue itself.
Continuing to learn about the challenges that face us today, continuing to research, and continuing to work together in a multidisciplinary effort is what will allow us to solve the problems that lay ahead.
References
Barbu, E. M., Cady, K. C., & Hubby, B. (2016). Phage Therapy in the Era of Synthetic Biology. Cold Spring Harbor Perspectives in Biology, 8(10). https://doi.org/10.1101/cshperspect.a023879
Brüssow, H. (2012). What is needed for phage therapy to become a reality in Western medicine? Virology, 434(2), 138–142. 10.1016/j.virol.2012.09.015
Blair, J. M. A., Webber, M. A., Baylay, A. J., Ogbolu, D. O., & Piddock, L. J. V. (2014). Molecular mechanisms of antibiotic resistance. Nature Reviews Microbiology, 13(1), 42–51. 10.1038/nrmicro3380
Chan, B. K., Abedon, S. T., & Loc-Carrillo, C. (2013). Phage cocktails and the future of phage therapy. Future Microbiology, 8(6), 769–783. https://doi.org/10.2217/fmb.13.47
Chan, B. K., Sistrom, M., Wertz, J. E., Kortright, K. E., Narayan, D., & Turner, P. E. (2016). Phage selection restores antibiotic sensitivity in MDR Pseudomonas aeruginosa. Scientific Reports, 6(1). 10.1038/srep26717
Fischetti V. A. (2018). Development of Phage Lysins as Novel Therapeutics: A Historical Perspective. Viruses, 10(6), 310. https://doi.org/10.3390/v10060310
Kortright, K. E., Chan, B. K., Koff, J. L., & Turner, P. E. (2019). Phage therapy: A renewed approach to combat antibiotic-resistant bacteria. Cell Host & Microbe, 25(2), 219–232. 10.1016/j.chom.2019.01.014
Lin, D. M., Koskella, B., & Lin, H. C. (2017). Phage therapy: An alternative to antibiotics in the age of multi-drug resistance. World Journal of Gastrointestinal Pharmacology and Therapeutics, 8(3), 162–173. 10.4292/wjgpt.v8.i3.162
Perry, J., Waglechner, N., & Wright, G. (2016). The Prehistory of Antibiotic Resistance. Cold Spring Harbor Perspectives in Medicine, 6(6). https://doi.org/10.1101/cshperspect.a025197
Ter Kuile, B. H., Kraupner, N., & Brul, S. (2016). The risk of low concentrations of antibiotics in agriculture for resistance in human health care. FEMS Microbiology Letters, 363(19). 10.1093/femsle/fnw210
UC San Diego Health. (n.d.). Phage 101. https://health.ucsd.edu/news/topics/phage-therapy/Pages/Phage-101.aspx
United Nations Interagency Coordination Group. (2019). No time to wait: Securing the future from drug-resistant infections. https://www.who.int/antimicrobial-resistance/interagency-coordination-group/IACG_final_report_EN.pdf?ua=1
W. A. Adedeji. (2016). The treasure called antibiotics. Annals of Ibadan Postgraduate Medicine, 14(2), 56–57. Retrieved September 29, 2020, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5354621/
World Health Organization. (2020, July 31). Antibiotic resistance. https://www.who.int/news-room/fact-sheets/detail/antibiotic-resistance#:~:text=Antibiotic%20resistance%20occurs%20when%20bacteria,caused%20by%20non%2Dresistant%20bacteria.
