Friday July 20 2018

The Superbug Apocalypse or: How I Learned to Stop Worrying and Love the Phage

In recent years, antibiotic resistance has become a loaded word in popular culture. When invoked, thoughts arise of an incurable plague sweeping across the globe and a return to a time when death from infection was common. Though such fears are probably overexaggerated, antibiotic resistance is still a very real problem. Each year in the United States, 2 million people are infected with antibiotic resistant bacteria and at least 23,000 people die as a result.[1] In Europe, around 25,000 deaths per year are also attributable to antibiotic resistance, adding a 1.5-billion-euro burden on healthcare and society.[2]

Although the most intuitive way to combat the developed antibiotic-immunity of bacteria is simply to develop novel drugs, numerous barriers exist that make this difficult. Innovation in antibiotics has remained relatively unprofitable due to the low return-on-investment for antibiotics and the high investment in R&D needed to develop new drugs, which has only increased with time.[3], [4] As a result, the number of antibiotic discoveries has declined in recent years.[5] Perhaps it is time to revisit therapies that have been left unexplored by a society enamoured with antibiotics.

Considered in the early 20th century as a potential treatment for infectious diseases, bacteriophages, often shortened to phages, are bacterial viruses. Discovered in 1916 by Félix d’Herelle, phage therapy has been practiced since 1919 when he first treated dysentery-infected children by administering dysentery-specific bacteriophages. [6], [7] Since then however, phage therapy has fallen out of favour due to the success of antibiotics. Nonetheless, therapeutic use of phages has continued in a limited capacity in the former Soviet Union and in Eastern European states. An English-language systematic review of these studies, made possible after the collapse of the Soviet Union, has found that lytic phages – phages that kill bacteria by breaking their membrane – have anti-microbial properties similar to antibiotics.[8] This review has similarly found that phages appear safe, with few reports of serious side effects.

Although research on phage therapy is scarce compared to the wealth of information on antibiotics, that which exists points to several advantages of bacteriophages over conventional antibiotics. Phages, being viruses, use the bacterium’s cellular machinery to replicate itself. As a result, more phages are produced as phage-infected bacteria die. Phages thus concentrate at the site of infection. Antibiotics, on the other hand, must circulate throughout the entire body and be present in relatively substantial amounts to be effective. Additionally, bacteriophages are host-specific and are unlikely to harm the microbiota in the patient’s body. Antibiotics are indiscriminate killers, targeting both helpful and harmful bacteria. Due to their host-specificity, phages are able to avoid inducing many of the side effects that antibiotics are prone to causing.

Most importantly, phage resistance is less pressing a problem than antibiotic resistance. Phages are driven by the same evolutionary pressures by which bacteria acquire antibiotic resistance.[9] Even under natural conditions, phages and bacteria are in an evolutionary arms race against one another, constantly struggling to overcome the counter-measures developed by the other. This means that the process of countering phage-resistant bacteria, or even discovering new phages, is a significantly quicker and cheaper process than developing new antibiotics.[10] As it is, phage therapy has not been implemented on as wide a scale as antibiotics, but nonetheless shows much promise as a tool to supplement or replace defunct antibiotics.

The potential of phage therapy is still relatively untapped, and there is much research that remains to be done. Knowing what we know now, phages present a very real opportunity for pushing back the return of infectious diseases.

The prospect of effective anti-microbials, able to combat antibiotic resistant bacteria, should be greeted with a sense of relief, but this sentiment should be tinged with caution. We have known for a long time about the possibility of antibiotic resistance developing yet have continued to overuse antibiotics regardless, both clinically and industrially. Even as early as 1945, Alexander Fleming, discoverer of penicillin, warned of “the danger that the ignorant man may easily under dose himself and by exposing his microbes [to antibiotics], … make them resistant”. [11] Innovation alone is not enough to safeguard against the development of resistance. Measures must be taken to conserve existing treatments for infectious diseases, even when the threat of resistance seems distant. Dulling the tools we already have by over-prescribing, only to frantically search for new ones when resistance inevitably arises, is not a sustainable process – especially as lives hang in the balance. Phage therapy may give us a second chance to avoid the superbug apocalypse. Let us not turn the clock back and repeat the mistakes of the past.

[1] Center for Disease Control and Prevention. Antibiotic/Antimicrobial Resistance. Available from: https://www.cdc.gov/drugresistance/ [Accessed: 23rd January 2018].

[2] European Commission. Antimicrobial Resistance. Available from: https://ec.europa.eu/health/amr/antimicrobial-resistance_en

[3] Wright GD. Something old, something new: revisiting natural products in antibiotic drug discovery. Canadian Journal of Microbiology. 2014;60(3): 147-154. DOI: 10.1139/cjm-2014-0063 [Accessed 23rd January 2018].

[4] Watkins JW. Fighting the Clock: Pharmaceutical and biotechnology companies seek ways to reduce the time required to discover and develop medicines. Chemical Engineering News. 2002;80(4): 27-44. DOI: 10.1021/cen-v080n004.p027 [Accessed 24th January 2018].

[5] Donadio S, Maffioli S, Monciardini P, Sosio M and Jabes D. Antibiotic discovery in the twenty-first century: current trends and future perspectives. The Journal of Antibiotics. 2010;63: 423-430. DOI: 10.1038/ja.2010.62 [Accessed 23rd January 2018].

[6] Duckworth DH. Who discovered bacteriophage?. Bacteriological Reviews. 1976;40(4): 793-802. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC413985/pdf/bactrev00054-0007.pdf [Accessed 23rd January 2018].

[7] Summers WC. Félix d’Herelle and the Origins of Molecular Biology. New England Journal of Medicine. 2000;342: 595. DOI: 10.1056/NEJM200002243420818 [Accessed 23rd January 2018].

[8] Sulakvelidze A, Alavidze Z and Morris JG Jr. Bacteriophage Therapy. Antimicrobial Agents Chemotherapy. 2001;45(3): 649-659. DOI: 10.1128/AAC.45.3.649-659.2001 [Accessed 24th January 2018].

[9] Ho K. Bacteriophage therapy for bacterial infections. Rekindling a memory from the pre-antibiotics era. Perspectives in Biology and Medicine. 2001;44(1): 1-16. DOI: 10.1353/pbm.2001.0006 [Accessed 14th January 2018].

[10] Loc-Carillo C and Abedon ST. Pros and cons of phage therapy. Bacteriophage. 2011;1(2): 111-114. DOI: 10.4161/bact.1.2.14590 [Accessed 23rd January 2018].

[11] Fleming A. Penicillin. [Lecture]. 11 December 1945. Available from: https://www.nobelprize.org/nobel_prizes/medicine/laureates/1945/fleming-lecture.pdf [Accessed 23rd January 2018].

Written by Kevin Zhao (Honours Health Sciences, Class of 2021)

Edited by Angela Dong (Honours Health Sciences, Class of 2020)


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