Exploiting the Evolutionary Trade-offs of Bacteria Through Phage Therapy and Antibiotics
Updated: Aug 30, 2020
By Jaden Bhogal, University of Toronto Schools, Ontario, Canada
Antimicrobial resistance (AMR) is the ability of a microorganism to resist antimicrobial treatments against it, resulting in persisted and oftentimes lethal infection in individuals. The World Health Organization (WHO) predicts that AMR has the potential to skyrocket into one of the largest global health issues humanity has ever faced. In their 2018 fact sheet, they mention how it will cause 10 million deaths annually by 2050, as well as US $100 trillion in economic losses (World Health Organization, 2018). AMR has greatly reduced the efficacy of antibiotics in treating bacterial infections. According to Benno. H. ter Kuile and colleagues from the Department of Molecular Biology and Microbial Food Safety at the University of Amsterdam, most AMR is caused by practices in the agricultural industry, making it an extremely complex and difficult problem to solve regardless of its urgency (ter Kuile, Kraupner & Brul, 2016). However, Kaitlyn Kortright and colleagues from Yale University and the Yale School of Medicine, posit that phage therapy - a novel medical treatment with renewed interest in Western medicine - has large potential as an effective solution for antimicrobial resistance in bacteria (Kortright, Chan, Koff & Turner, 2019).
Benno H. ter Kuile and his colleagues agree there is a distinct correlation between the use of sublethal levels of antibiotics in agriculture and the generation of resistant pathogens. It is estimated that 50% - 80% of all AMR comes from agriculture, whether it be directly from food production or environmental transmission (ter Kuile et al., 2016). Ter Kuile and colleagues suggest that the use of antibiotics as growth hormones, prophylactics, or hygienic agents are unregulated and are often given in smaller-than-lethal doses (ter Kuile et al., 2016). This provides the necessary selection pressure for the small number of surviving bacteria to evolve multidrug resistance (MDR) genes and share them with other bacterial colonies through horizontal gene transfer (ter Kuile et al., 2016).
The effects of these practices are already widespread. According to the WHO, antibiotic resistance is present in every country in the world, putting an increasing strain on their healthcare system as more infections occur (World Health Organization, 2018). In 2019, there were 2.8 million resistant infections across the United States alone, resulting in over 35,000 deaths: an alarming increase from the 23,000 deaths in the previous year (Centers for Disease Control and Prevention, 2020). Sharp increases such as these have warranted the development of global action plans to improve the delivery and use of antibiotics. At the WHO’s Sixty-eighth World Health Assembly in 2015, initiatives such as antimicrobial optimization, stewardship, and research into new types of antibiotics were implemented worldwide. These involve the enhanced supervision of antibiotic prescriptions, as well as investing resources into creating new classes of antibiotics that are more capable of treating resistant infections (World Health Organization, n.d.).
Unfortunately, these initiatives are already facing increasing limitations. Out of the estimated 480,000 cases of multidrug-resistant tuberculosis (MDR-TB) across the globe in 2014, it is thought that 3.3% of them were caused by extensively drug-resistant tuberculosis (XDR-TB), a form of TB which is resistant to four or more anti-TB drugs. In recent years, this proportion has risen to 9.7%, displaying the rapid increase in antibiotic resistance in dangerous bacteria despite global action against this (World Health Organization, 2018). Additionally, the American Society for Microbiology (ASM) announced the emergence of bacteria that are resistant to colistin, which is currently the strongest antibiotic available (Reardon, 2017).
Reassuringly, Kaitlyn E. Kortright and her colleagues pose phage therapy as a high potential treatment method for superbug infections (Kortright et al., 2019). This involves small viruses called bacteriophage, which naturally infect bacterial cells. The phage selectively bind to certain proteins on the bacterial membrane, insert their genome into the bacterial host, hijack its metabolism to produce phage progeny, and lyse the bacterial cell releasing thousands of more phages into the environment and repeating the cycle (Kortright et al., 2019). Phages come in many different varieties, and this variety determines which type of bacteria they will bind to. This is a useful means for phage therapy to be a precision medicine treatment (Kortright et al., 2019). Phages and bacteria are in a constant state of coevolution, continually evolving resistance against one another to survive. Kortright and her colleagues argue that this can be heavily exploited to improve phage therapy treatments (Kortright et al., 2019). Specialized bacterial cellular machinery, such as efflux pumps, allow them to more easily resist antibiotics. Kortright and her colleagues mention how when certain phages bind to these structures, the bacterial colony will remove them in subsequent generations so no further binding can occur (Chan, Sistrom, Wertz, Kortright, Narayan & Turner, 2016). This, however, reduces the bacteria’s antibiotic resistance or virulence, now rendering antibiotics effective against it (Chan et al., 2016). By using compound treatments such as phage-antibiotic therapy, the evolutionary trade-offs of bacteria can be exploited to cure complex infections (Kortright et al., 2019).
Currently, phage therapy has had a lot of success in treating lethal MDR infections where antibiotics alone have failed. Benjamin K. Chan and his colleagues highlight this in an aortic graft infection case report, where three years of suppressive antibiotic therapy failed to treat a patient with a superbug infection (Chan et al., 2016). Chan and colleagues used bacteriophage OMKO1 along with the antibiotic ceftazidime intravenously, and after two years of treatment the patient recovered (Chan et al., 2016). This provides hope that using phage therapy in conjunction with antibiotics will be able to mitigate the negative effects of antibiotic resistance in the future.
Centers for Disease Control and Prevention. (2020, March 13). Antibiotic / Antimicrobial Resistance (AR / AMR). https://www.cdc.gov/drugresistance/biggest-threats.html
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). doi:10.1038/srep26717
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. doi:10.1016/j.chom.2019.01.014
Reardon, S. (2017, June 12). Resistance to last-ditch antibiotic has spread farther than anticipated. Nature. https://www.nature.com/news/resistance-to-last-ditch-antibiotic-has-spread-farther-than-anticipated-1.22140
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). doi:10.1093/femsle/fnw210
World Health Organization. (2018, February 5). Antibiotic Resistance. Retrieved from https://www.who.int/news-room/fact-sheets/detail/antibiotic-resistance
World Health Organization. (n.d.). Global action plan on antimicrobial resistance. Retrieved May 16, 2020, from https://www.who.int/antimicrobial-resistance/global-action-plan/en/