• Triple Helix

The Search for Next Generation Antibiotics: Bacteriophages

Written by William Boyce '26

Edited by Anusha Srinivasan '24


Part 1: Introduction & Antibiotic-Resistance Crisis

Since their discovery in 1928 by Sir Alexander Fleming, antibiotic medications have commonly been used to combat bacterial infections, a condition in which pathogenic bacteria overrun an individual’s immune system and wreak havoc upon the body. Typically, antibiotics obstruct essential mechanisms in bacteria, consequently neutralizing their reproductive capability and halting their spread. During the so-called “golden era” of antibiotics between 1950 and 1970, the leading cause of death in the United States shifted from communicable diseases, many of which were bacterial infections, to non-communicable diseases, such as cardiovascular disease and cancer [1].


Unfortunately, modern civilization currently exists in the post-antibiotic era– a critical time in which humanity faces an unprecedented and ever-escalating arms-race with bacteria. Antibiotic resistance, or bacteria’s capability to overcome the effects of antibiotics they were once sensitive to, represents an increasingly urgent topic of medical concern. According to the U.S. Centers for Disease Control and Prevention, “more than 2.8 million antibiotic-resistant infections occur in the United States each year, and more than 35,000 people die as a result” [2]. Although antibiotics have saved countless patients’ lives since their discovery, systemic over-prescription and misuse has encouraged rampant mutations, some of which lead to antibiotic resistance, within targeted bacterial communities. Because antibiotic-resistant bacteria possess a competitive advantage, selection pressure promotes the proliferation of mutated bacterial strains, thereby accelerating their dominance within bacterial communities. Moreover, bacteria’s ability to conduct horizontal gene transfer, the transport of genetic information between microbes, further fuels the spread of antibiotic resistance genes among bacteria [3]. Collectively, these factors represent the major driving forces of antibiotic resistance.


Due to traditional antibiotics’ curtailed effectiveness, humans must now look towards the development of new tools to aid in the fight against bacteria. Taking inspiration from mother-nature, scientists have turned towards bacteriophages as the potential future generation of new-age antibiotics.


Part 2: Introduction to Bacteriophage Structure & Function

Bacteriophages constitute one of the most abundant life-forms on Earth, as they are common in a myriad of environments, including everything from regular soils, processed sewage, and all bodies of water. True to their name, bacteriophages are viral nano-machines that infiltrate, infect, and hijack bacteria, capitalizing upon their molecular resources to fuel their own propagation. To coordinate these reproductive mechanisms, bacteriophages possess thousands of different morphologies, but the most studied group, especially in regards to overcoming antibiotic-resistant bacteria, remains that of tailed phages (order Caudovirales) [4]. Caudovirales is further classified depending on tail type, as Siphoviridae possesses a long non-contractile tail, Podoviridae possesses a short non-contractile tail, and Myoviridae possesses a complex contractile tail [4].


In general, three principle components comprise tailed phages– a genome-storing capsid, a long tail-like shaft for injecting the genome into host cells, and an adhesive apparatus that identifies and binds to host cells. The bacteriophage genome consists of either single-stranded or double-stranded DNA or RNA. Additionally, bacteriophages typically have a head-to-tail interface, which consists mainly of a specialized portal protein within the capsid [4].


Part 3: Summary of Bacteriophage Function

Like all viruses, bacteriophages are specific particles, meaning that each bacteriophage type infects particular host cells. Initiating its self-assembly cycle, a bacteriophage initially utilizes its adhesive apparatus to attach to a susceptible host, then undergoes a certain replication process: either lytic or lysogenic [5]. Within lytic replication, a bacteriophage injects its genome into the host bacteria’s cytoplasm, then utilizes its ribosome and cellular resources to produce new bacteriophage genomes and capsid proteins, which are then assembled into new copies of the original bacteriophage [5]. At the end of the lytic replication cycle, the host cell is lysed to release the bacteriophage copies into the extracellular matrix and infect other hosts. Conversely, lysogenic replication relies upon identical self-assembly mechanisms as lytic reproduction, except that the bacteriophage genome instead integrates into the host’s genome without killing it [5]. As a result, the bacteriophage genome is passed along generations of bacteria, constantly producing bacteriophage components. However, specific environmental conditions can induce lysogenic bacteriophages to conduct lytic replication, consequently killing all hosts with the integrated bacteriophage genome [5].


Part 4: Conclusion & How Bacteriophages Could Solve the Antibiotic-Resistance Crisis

Overall, bacteriophages possess numerous advantages over traditional antibiotics. Not only are bacteriophages extremely specific in the bacteria they target, but they are also capable of mutating in response to selective pressure from bacteria [6]. Consequently, if bacteria somehow developed resistance to bacteriophages in the future, bacteriophages would similarly co-evolve to overcome this resistance.


Despite bacteriophage’s promising antibacterial mechanisms, additional research is needed to truly validate their efficacy within humans. In a randomized, controlled, and double-blind clinical phase ½ trial posted in The Lancet Infectious Diseases, researchers investigated the effectivity of an anti-P aeruginosa bacteriophages in 27 patients with established burn-wounds infected with P aeruginosa bacteria [7]. However, the study determined that at very low concentrations , the bacteriophages “decreased bacterial burden in burn wounds at a slower pace than standard of care… [so] increased phage concentrations… in a larger sample of participants are warranted” [7]. Thus, although the current state of bacteriophage treatment remains a work-in-progress, such research results prompts additional, future testing. Additionally, more research is needed to establish bacteriophage’s efficacy in antibiotic-resistant bacterial populations. Consequently, while bacteriophage therapy is not currently a reality, it still remains at the forefront of humanity's “arms-race” with antibiotic resistance.

 

References

1. Adedeji WA. THE TREASURE CALLED ANTIBIOTICS. Ann Ib Postgrad Med. 2016 Dec;14(2):56–7.

2. Centers for Disease Control and Prevention (U.S.). Antibiotic resistance threats in the United States, 2019 [Internet]. Centers for Disease Control and Prevention (U.S.); 2019 Nov [cited 2022 Oct 28]. Available from: https://stacks.cdc.gov/view/cdc/82532

3. Burmeister AR. Horizontal Gene Transfer. Evol Med Public Health. 2015 Jul 29;2015(1):193–4.

4. White HE, Orlova EV, White HE, Orlova EV. Bacteriophages: Their Structural Organisation and Function [Internet]. Bacteriophages - Perspectives and Future. IntechOpen; 2019 [cited 2022 Oct 28]. Available from: https://www.intechopen.com/state.item.id

5. Kasman LM, Porter LD. Bacteriophages. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 [cited 2022 Oct 30]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK493185/

6. Sulakvelidze A, Alavidze Z, Morris JG. Bacteriophage Therapy. Antimicrob Agents Chemother. 2001 Mar;45(3):649–59.

7. Jault P, Leclerc T, Jennes S, Pirnay JP, Que YA, Resch G, et al. Efficacy and tolerability of a cocktail of bacteriophages to treat burn wounds infected by Pseudomonas aeruginosa (PhagoBurn): a randomised, controlled, double-blind phase 1/2 trial. The Lancet Infectious Diseases. 2019 Jan 1;19(1):35–45.



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