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Bacteriophage vs Superbug: Who Will Win?

A pink, cartoon ice cream cone with a worried expression is sitting on a bed of ice with icicles along its cone. Two blue protein characters flank the ice cream wearing medical caps and carrying first aid kits. The right protein is also carrying a bag labelled “ANTI FREEZE”. A blue icicle frame is drawn and in the background is a girl with a shocked expression, looking at the ice cream and proteins in the foreground.

Written by Anne-Marie Bulboaca
Edited by Medha Sarker
Illustrated by Amelia Han

Invisible to the eye and resistant to every antibiotic in our arsenal, the “superbug” is a deadly manifestation of the antibiotic resistance crisis. This term is broadly used to refer to pathogenic bacteria that have evolved resistance to a wide variety of antibiotics, making infections by these bugs extremely challenging to treat. They can result in prolonged illnesses and have an increased risk of mortality1,2. In 2019, the World Health Organization declared antibiotic resistance a top 10 global health threat2. By 2050, global deaths attributable to (directly caused by) antimicrobial resistance are projected to reach 1.9 million, while deaths associated with (indirectly or potentially caused by) antimicrobial resistance could total as many as 8.2 million3. The pressing issue of antibiotic resistance has initiated a wave of research aiming to discover new methods of treating bacterial infections.

One fascinating example has been the development and application of phage therapy. This treatment harnesses the bacterial killing power of bacteriophages, naturally occurring viruses that infect bacteria. These are the oldest and most abundant organisms on the planet, having co-evolved alongside their bacterial hosts for nearly 4 billion years4. They were independently discovered by two researchers: Frederick Twort in 1915 and Félix d’Hérelle in 19171. Before penicillin use became widespread, phages were used extensively to treat infections in both humans and animals4. The first phage therapy programs opened in Georgia and Poland and remain open today. However, the widespread use of penicillin during WWII and distrust of the Soviet Union caused phage therapy to fall out of favour in the west, until now. Phage therapy is being studied around the world, with an increasing number of successful patient cases demonstrating its promise as an up-and-coming treatment.

Like all viruses, bacteriophages cannot replicate independently, as they require the machinery of a host to replicate their genome and produce viral proteins4. A phage consists of genetic material (DNA or RNA) encased in a protein structure called a capsid, resembling a head. The most common phages also have a tail structure that allows them to attach to receptors or other components on the bacterial cell wall and inject their genome into the intracellular space5. Because this process is receptor-mediated, each phage can infect only certain bacteria, determined by the expression of receptors it can bind to4.

2 small blue antifreeze proteins wearing medical caps are seen standing ontop of a pink ice cream cone, grabbing ice shards on its surface. One protein is seen holding two ice shards and throwing them off the side towards another protein on the floor. Beside it, is a brown box of ice shards.

Phages have two possible life cycles: lytic or temperate. Upon infection, lytic phages have their genome immediately replicated using host machinery, new phages are assembled, and the bacteria is lysed so they can infect a new host. Temperate phages can follow either the lytic or lysogenic path4. In lysogeny, the phage remains dormant in the bacterial host as a prophage, allowing the host to grow for a period before the lytic process is initiated. Because lysogeny does not immediately result in bacterial death, only lytic phages are suitable for therapeutic use.

The biological features of phages reflect both opportunities and challenges in phage therapy research. The specificity of phage infection is both a strength and a drawback; phages can target a certain pathogen while sparing the microbiome, but treatment requires knowledge of which pathogens are driving the infection and the selection of phages that target them1. Fixed phage therapy, in which preformulated phage preparations target specific bacteria, would be a convenient form of treatment. However, this method has shown limited success in clinical trials. In contrast, personalized phage therapy, in which phages are specifically chosen to target a patient’s infecting strains, has been successful in many high-profile cases. Another challenge is the need for lytic phages, which limits the number of options available. Most importantly, the co-evolution of phages and bacteria can result in phage resistance, as bacteria develop new methods to evade or prevent phage infection (eg. CRISPR/Cas9-mediated breakdown of phage DNA) while phages simultaneously adapt stronger mechanisms of infection. Interestingly, studies have shown that when bacteria gain phage resistance, they may become more sensitive to certain antibiotics, a prime example of an evolutionary trade-off6.

To overcome these challenges, scientists have developed fascinating methods of manipulating the properties of phages to better suit treatment needs. For instance, genetic tools like CRISPR/Cas9 have allowed researchers to edit phage genomes. Changes can be as minor as deleting lysogeny genes to ensure phages enter the lytic cycle, or as grand as synthesizing new phages completely from scratch6. To combat phage resistance, phages are often administered in cocktails, with multiple phages targeting a single bacterial species, as resistance is unlikely to arise against all the phages at once. In a case published in 2019, a teenage cystic fibrosis patient suffering from a severe lung infection was successfully treated with a three-phage cocktail, including one phage which was genetically engineered to improve the efficiency of bacterial elimination7. These methods are being applied successfully in the clinic, showing promise for treating infections that might otherwise be incurable.

Phage therapy represents a powerful weapon in the fight against antibiotic resistance. Its precision, engineering potential, and growing clinical successes showcase exciting opportunities, while challenges like high host specificity and the risk of resistance remain significant hurdles. Ongoing innovation and careful application will determine how effectively phage therapy can combat superbugs.

References

  1. Olawade DB et al. Phage therapy: A targeted approach to overcoming antibiotic resistance. Microbial Pathogenesis. 2024;197:107088. https://doi.org/10.1016/j.micpath.2024.107088
  2. EClinicalMedicine. Antimicrobial resistance: a top ten global public health threat. eClinicalMedicine. 2021 [accessed 2025 Nov 21];41. https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(21)00502-2/fulltext. https://doi.org/10.1016/j.eclinm.2021.101221
  3. Naghavi M et al. Global burden of bacterial antimicrobial resistance 1990–2021: a systematic analysis with forecasts to 2050. The Lancet. 2024;404(10459):1199–1226. https://doi.org/10.1016/S0140-6736(24)01867-1
  4. Strathdee SA, Hatfull GF, Mutalik VK, Schooley RT. Phage therapy: From biological mechanisms to future directions. Cell. 2023;186(1):17–31. https://doi.org/10.1016/j.cell.2022.11.017
  5. Dowah ASA, Clokie MRJ. Review of the nature, diversity and structure of bacteriophage receptor binding proteins that target Gram-positive bacteria. Biophysical Reviews. 2018;10(2):535–542. https://doi.org/10.1007/s12551-017-0382-3
  6. Kim MK et al. Bacteriophage therapy for multidrug-resistant infections: current technologies and therapeutic approaches. The Journal of Clinical Investigation. 135(5):e187996. https://doi.org/10.1172/JCI187996
  7. Dedrick RM et al. Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus. Nature Medicine. 2019;25(5):730–733. https://doi.org/10.1038/s41591-019-0437-z

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