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Spring 2021
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Could the cure we’re looking for be in in our own backyard? 

By Divyam Goel, Undergraduate Student at the University of Utah

The COVID-19 pandemic has rattled developed and developing societies alike, across the globe, bringing to attention the powerful impact a microscopic organism can have should it be able to roam unchecked. It serves as inspiration to carefully evaluate, with a discerning and skeptical eye, whether humanity is truly in control of the microbial world, and whether our actions can exacerbate an already prolific problem.

Historical examples of microorganisms dominating humanity abound and, while we usually manage to pull through, there are notable occasions where our retaliation actually costs lives. In my opinion, there is no better example of such a mishap as the shrouded pandemic of antibiotic resistance, a dark horse in the ever-relevant world of infection control. Yet, there is hope, and the key to managing this growing concern could lie in our own backyard – wastewater treatment plants. 

Antibiotic resistance refers, broadly, to any developed resistance from pathogenic, or infectious, bacteria towards antibiotics commonly used. Once an obscure problem observed in isolated species here and there, more and more infectious pathogens are noted to show antibiotic resistant behavior. In fact, microorganisms have been known to develop resistance within months to several years of the approval of a new antibiotic. According to the Center for Disease Control and Prevention, a methicillin resistant strain of Staphylococcus aureus was isolated in 1960, the same year methicillin was approved for distribution. A cephalosporin resistant E. coli was identified in 1983, three years after extended-spectrum cephalosporin approval. Klebsiella pneumonia was found in 2015 to be resistant to a Ceftazidime-avibactam a few months following its release. Several other common organisms such as Pseudomonas aeruginosa, a recurrent bacterium that usually affects those hospitalized for surgery, and Mycobacterium tuberculosis, the namesake organism accountable for tuberculosis disease, pose antibiotic resistant infections, or even multi-drug resistance (resistance to more than one antibiotic) in various patients. These resistant infections are credited with almost 700,000 deaths annually, more than 25,000 of which are in the US; this number grows every year. 

While antibiotic resistant organisms are almost invalidating the effort to work towards newer antibiotics (which still see organisms demonstrating resistant soon after clinical availability), there is a way out, and one that often sits deep inside the gallons of municipal wastewater many of our water treatment community members work to manage and control. I am speaking of bacteriophages or, simply, phages. Phages are small viruses that infect bacterial cells to reproduce, and have been shown in studies dating back to the era of pre-molecular medicine prior to World War I, to easily lyse, or kill, bacterial cells. While several types of phages exist, and are actually by a large margin the most populous organism on the planet, none are harmful to humans because they simply cannot infect a human cell. Another notable characteristic that phages are known to feature is their ‘host-specificity’, or the mechanism that one species of phage is able to infect only one bacterial species. Bacteriophages have tail proteins that recognize specific surface features on the particular bacterial specie that they will infect. This specificity means phages don’t have any major side effects noted with normal clinical treatment. Anyone who has taken antibiotics for an infection is familiar with the stomach problems commonly associated with it, which comes from the indiscriminate killing of any bacteria including helpful strains found in the gut. Phage therapy keeps these gut microbiomes intact.

Phages have been shown to be highly effective in lab models with dangerous multi-drug resistant organisms, and are even able to combat bacterial defense such as biofilms, or a secretion of polysaccharide coating bacteria encase themselves in to stay hidden and protected. Biofilms inside of organs such as lungs are an issue many patients with underlying conditions have died from. Phage therapy has been shown to also offer significant levels of success in treating infected mouse models, where researchers replicate various infections artificially. It has even been used in isolated cases here and there in humans as a last resort treatment, often for skin infections, urinary tract infections, and other cases where antibiotics were declared nearly useless, and many patients have fully recovered. A final benefit is that phages do not need to be manufactured; they already exist in the environment, preying on their bacterial hosts. Wastewater reservoirs are a common search site for phage, and I, myself, have easily isolated phages for multi-drug resistant Pseudomonas and Staphylococcus from Central Valley primary sludge and effluent. 

Phage therapy is not just limited to medical problems – as shown above, wastewater is a common reservoir for phage yet it has also been demonstrated for use in wastewater engineering applications. There are notable studies coming out of Utah itself. For example, Bhattacharjee et al. 2015 from the University of Utah demonstrated the use of phage therapy to kill bacterial biofilms developing in a membrane bioreactor, showing much reduced biofouling of the membranes. Similar studies note the efficacy of phages in bioengineering applications. 

All this talk of benefits and successes leads one to ask ‘why is phage therapy not the norm?’ The answer lies mostly in its history; biological therapies have always maintained controversy and falsification, and this trend persists. The United States FDA does not easily permit biological research, especially therapeutics such as phage, that are biological themselves. There is the added problem of quantity – antibiotics can be produced in large amounts quite fast while phage farming is a much slower ordeal, given the fact that phage need healthy hosts to prey on to proliferate. It is one of the main reasons why antibiotics actually passed phage in popularity in the early 20th century; soldiers fighting in World War I needed treatment for their infections faster than phage therapy could provide. 

Yet, society calls for our researchers to do better. Antibiotic resistance is, to me, the pinnacle example of ‘shooting yourself in the foot’, and a mistake that is costing thousands of lives. Phage therapy promises an evolutionarily successful predator-prey relationship that we can, and have been able to, piggyback on. Proponents of phage therapy have been requesting Randomized Clinical Trials (RCTs), the investigative procedure that any drug, therapy or vaccine must pass through to gain FDA approval, for years. It is high time for us to do so and turn the tide on preventable infection deaths. As the saying goes, ‘an enemy of my enemy is my friend’.

References

Bhattacharjee, A. S., Choi, J., Motlagh, A. M., Mukherji, S. T., & Goel, R. (2015). Bacteriophage therapy for membrane biofouling in membrane bioreactors and antibiotic-resistant bacterial biofilms. Biotechnology and Bioengineering.

Botelho, J., Grosso, F., & Peixe, L. (2019). Antibiotic resistance in Pseudomonas aeruginosa – Mechanisms, epidemiology and evolution. Drug Resistance Updates.

Casjens, S. R. (2008). Diversity among the tailed-bacteriophages that infect the Enterobacteriaceae. Research in Microbiology, 1-9.

Centers for Disease Control and Prevention. (2020, March 13).
About Antibiotic Resistance. Retrieved from Centers for Disease Control and Prevention: www.cdc.gov/drugresistance/about.html.

Summers, W. C. (2012). The strange history of phage therapy. Bacteriophage, 130-133.

Todar, K. (n.d.). The Bacteriophages. Retrieved from Todar’s
Online Textbook of Bacteriology: www.textbookofbacteriology.net/phage.html.

Wright, A., Hawkins, C., Anggard, E., & Harper, D. (2009).
A controlled clinical trial of a therapeutic bacteriophage preparation in chronic otitis due to antibiotic-resistant Pseudomonas aeruginosa; a preliminary report of efficacy.
Clinical Otolaryngology.

Young, R., & Gill, J. J. (2015). Phage therapy redux – What is to be done? Science, 1163-1164. 

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