Bacteriophages: A Viral Cure for Antibiotic Resistance?
Part 1 of a two-part series on phages and their many uses. Part 1 focuses on medical uses, while part 2 will focus on environmental, agricultural, industrial, and food safety applications.
The Resurrection of a Century-Old Cure
Antimicrobial resistance (AMR) is proving to be one of the greatest public health challenges of our time. In the Western Pacific region alone, AMR is projected to be the cause of 5.2 million deaths by the start of the next decade1. This has the potential to completely outpace public health interventions and investments into cures. Routine treatments for infections are becoming increasingly ineffective, with the urgency to find alternatives having never been greater..
One contender to fill this gap is bacteriophages. Bacteriophages (phages for short) are viruses that specifically infect and destroy bacteria. Phages were once hailed as a miracle cure during their heyday in the early 20th century. They treated infections ranging from dysentery to septic wounds, and apparently with remarkable precision, especially when compared to antibiotics broad-spectrum actions 2. But another miracle cure stole the spotlight with the rise of penicillin and other antibiotic therapies in the 1940’s, completely overshadowing phage therapy and relegating it to niche applications in Eastern Europe and the former Soviet Union3
As AMR accelerates and the development of new antibiotics somewhat lags behind, phage therapy is making a cautious but compelling comeback. Scientists in genomics and synthetic biology tools to the table that have equipped phages with incredible precision to combat drug-resistant bacteria4. Success stories, including patients being saved from near-fatal infections by tailored phage cocktails, hint at their ability to revolutionize the treatment of infectious diseases. However, significant challenges remain. Some studies have found bacteria becoming resistant to phages in a way that is eerily reminiscent of antibiotic resistance. Regulatory hurdles make the research a bit difficult to get done. And scalability is always an issue to consider with new drugs.
In this post I’ll explore the rise, fall, and resurrection of phage therapy from its intriguing history and breakthroughs to the challenges and promises that define its range of uses.
The Rise and Fall of Phage Therapy
The story of phage therapy starts with Felix d’Herelle, the self-taught French-Canadian scientist who discovered bacteriophages in 19175. d’Herelle was a brilliant man but with a relentless conviction, two traits that would end up defining both his successes and struggles. Fresh off his discovery of phages in the diarrhea of locusts in Mexico, he returned to Paris and identified similar viruses in the stool samples of French soldiers with dysentery. By 1919 he had successfully treated a patient using phages, solidifying their therapeutic potential and earning him international recognition2,3.
d’Herelle’s advocacy for phage therapy was relentless and somewhat polarizing. His claim went beyond phages being an antimicrobial tool. He asserted that they were the true driver of natural recover and relegated the immune system to a secondary role. This stance alienated much of the medical establishment, as it was seen as an overreach not grounded in the scientific consensus of that era or today6. But it was his charisma and enthusiasm that launched phage therapy into clinical practice worldwide during the interwar years.
After some setbacks in France, d’Herelle got a ray of hope when an invitation to the Soviet Union and funding from Joseph Stalin came his way in 1934. Partnering with the Georgian microbiologist George Eliava, d’Herelle helped establish the Tbilisi Institute (Later renamed the George Eliava Institute), a center still dedicated to phage research. In a turn of events fitting of Soviet Russia, Eliava had personal conflicts with Lavrenti Beria, Stalin’s future secret police chief, that led to his execution and d’Herelle’s fleeing back to France. His death in 1949 was overshadowed by the rise of penicillin and other antibiotic therapies.
Let’s be clear though, the decline of phage therapy in the West wasn’t a simple product of the allure of antibiotics. The uncompromising vision and unwillingness to align his claims with broader medical paradigms contributed to its sidlining3. Despite these setbacks, phage therapy thrived in Eastern Europe and the Soviet Union. So much so that the institute remains a global leader in phage research to this day. It’s extensive phage library serves as a beacon of hope for patients with drug-resistant infections.
As AMR looms as a threat to modern medicine, d’Herelle’s vision is finding renewed relevance. His journey of discovery and controversy offers an excellent lense to view both the upsides and the downsides of phage therapy. Papers with titles like “Phage Are All the Rage”, “Phage Therapy: An alternative to antibiotics in the age of multi-drug resistance” and “Phage therapy as a viable solution in the fight against AMR” are becoming increasingly more frequent, signaling a renaissance in the area. Whether d’Herelle’s work ultimately provides the necessary tools for combating AMR or should be seen as a cautionary tale of unchecked scientific enthusiasm, one thing is certain. The story of phage therapy is far from over.
The Modern Resurgence of Phage Therapy
The reignited interest in phage therapy in light of the challenges of antimicrobial resistance has prompted researchers and clinicians to revisit this century old solution. Armed with the modern tools of synthetic biology, genomics, machine learning, and personalized medicine, scientists are using phages in precision medicine. The field is overflowing with cautious optimism due to recent success stories and the innovative approaches phages allow for.
The Tools
These modern technologies equip researchers with unprecedented tools to study and modify phages. Genomic sequencing allows for the identification of specific mechanisms by which phages bind to bacteria, enhancing the ability to tailor phage cocktails for personalized treatments7. Synthetic biology goes a step further, enabling the engineering of phages to bypass bacterial resistance mechanisms like CRISPR systems, bacterial defense mechanisms that can recognize and destroy invading genetic material, that some bacterial species use as a defense against phages8. Machine learning algorithms are being used to predict phage-bacterial interactions, helping to speed up the process of identifying effective combinations and cocktails9. Our current technological renaissance has shifted the perception of phages from obscure natural phenomena to a viable therapeutic.
Compassionate Use and Clinical Trials
Some of the most remarkable stories of phage therapy come from “compassionate use” protocols, where treatments are given to critically ill patients with no other options. One such case involved a patient with a life-threatening Acinetobacter baumannii infection. The 68 year-old patient with a history of diabetes and necrotizing pancreatitis was saved through a custom phage cocktail10. The success of these personalized treatments is inspiring greater investment in clinical trials evaluating the broader efficacy and portability of phage therapies.
As always though, challenges remain. Many phage therapies remain in the experimental stage, hindered by the need for individualized treatments and a lack of standardized manufacturing processes for new phage therapies11. Another hurdle is regulatory approval, as traditional frameworks designed for drug evaluation often struggle to accommodate the ever-changing and tailored nature of phage therapy12. The promising case studies highlight the possible uses of phage therapy, but widespread adoption will require overcoming several barriers and collaboration among biotech companies, hospitals, and academic institutions.
Some Key Players in Phage Development
Biotech companies and academic institutions are working to address those limitations. In March of 2024, BiomX Inc., a clinical-stage company announced the acquisition of, and $50 million in funding to, Adaptive Phage Therapeutics. They aim to use this funding, and hopefully much more in the future, to create a leading phage therapy pipeline, including two Phase 2 trial assets: BX004 for treating chronic pulmonary infections in patients with cystic fibrosis and BX211 for diabetic foot osteomyelitis13. As for the scalability issues, BiomX uses a fermentation-based production method, which s said to be more cost-effective and scalable than traditional approaches. They are also exploring synthetic production methods and AI to predict which phages will be most effective. Felix Biotechnology is developing engineered phages with enhanced potency and broader targeting capabilities. More groups like PHAXIAM, Intralytix, Locus Biosciences, and more are all working on new and improved phage therapies to address AMR.
Standardization of phage therapy regimens is also gaining traction, with efforts being made to establish “phage committees” who aim to coordinate and standardize the products, protocols, production methods, and regulatory processes. Genetic engineering techniques should further enhance the efficiently in production lines by increasing phage titers and making production at a large-scale much more feasible.
Despite these advancements, concerns remain about the scalability of phage therapies. Unlike antibiotics that can be mass-produced with relative ease, phage production requires incredibly intricate matching of phages to specific bacterial strains. These qualities present logistical and economic challenges, especially in more resource limited settings.
A Complement to Antibiotic Therapies
Phage therapy, while gaining recognition, is a promising complement to antibiotics, not a full-blown replacement. By combining phages with traditional antibiotics researchers are hoping to develop synergistic treatments to minimize resistance while maintaining maximum levels of efficacy. Preliminary studies have shown these combinations can restore the efficacy of drugs that bacteria had previously resisted4,8. As we stand on the brink of a post-antibiotic era, phages represent a critical piece of the infrastructure addressing AMR. They may not be a panacea, but they have massive potential in helping address the AMR crisis. With continued innovation and investment, phage therapy could become a cornerstone of 21st century medial practice.
The Future of Phage Therapy
Phage therapy, after being sidelined by the rise of antibiotics, is experiencing a vast renaissance that is long overdue. The precision ability to target drug resistant bacteria with the support of advancements in genomics, synthetic bio, and AI makes this a critical tool to address the AMR crisis. The road ahead requires global collaboration and sustained investment, as well as new regulatory frameworks, to make phage therapy scalable.
No, phages are not going to fix the AMR crisis over night. But they bring substantial advantages to the table. They are a versatile complement to antibiotics. They can reinvigorate failing treatments. And they are a highly adaptable approach to infectious disease treatment and management. Innovation and committment could see phage therapy becoming one of the most important treatment paradigms of this century. The work to remove AMR as a threat to public health is long from over. Phages are one of the most promising innovations in infectious disease treatment and seems poised to play a key role in addressing the AMR problem.
Citations
1. Antimicrobial resistance expected to cause 5.2 million deaths in the Western Pacific by 2030. Accessed January 6, 2025. https://www.who.int/westernpacific/news/item/13-06-2023-antimicrobial-resistance-expected-to-cause-5.2-million-deaths-in-the-western-pacific-by-2030
2. Summers WC. The strange history of phage therapy. Bacteriophage. 2012;2(2):130-133. doi:10.4161/bact.20757
3. Fruciano DE, Bourne S. Phage as an antimicrobial agent: d’Herelle’s heretical theories and their role in the decline of phage prophylaxis in the West. Can J Infect Dis Med Microbiol. 2007;18(1):19-26.
4. Hibstu Z, Belew H, Akelew Y, Mengist HM. Phage Therapy: A Different Approach to Fight Bacterial Infections. Biol Targets Ther. 2022;16:173-186. doi:10.2147/BTT.S381237
5. Fisher LM. Bacteriophages to the Rescue? Milken Institute Review. Accessed January 6, 2025. https://www.milkenreview.org/articles/bacteriophages-to-the-rescue
6. Summers WC. Félix Hubert d’Herelle (1873–1949): History of a scientific mind. Bacteriophage. 2017;6(4):e1270090. doi:10.1080/21597081.2016.1270090
7. Hatfull GF, Dedrick RM, Schooley RT. Phage Therapy for Antibiotic-Resistant Bacterial Infections. Annu Rev Med. 2022;73(Volume 73, 2022):197-211. doi:10.1146/annurev-med-080219-122208
8. Oechslin F. Resistance Development to Bacteriophages Occurring during Bacteriophage Therapy. Viruses. 2018;10(7):351. doi:10.3390/v10070351
9. Cui L, Kiga K, Kondabagil K, Węgrzyn A. Current and future directions in bacteriophage research for developing therapeutic innovations. Sci Rep. 2024;14(1):24404. doi:10.1038/s41598-024-76427-5
10. Schooley RT, Biswas B, Gill JJ, et al. Development and Use of Personalized Bacteriophage-Based Therapeutic Cocktails To Treat a Patient with a Disseminated Resistant Acinetobacter baumannii Infection. Antimicrob Agents Chemother. 2017;61(10):10.1128/aac.00954-17. doi:10.1128/aac.00954-17
11. Furfaro LL, Payne MS, Chang BJ. Bacteriophage Therapy: Clinical Trials and Regulatory Hurdles. Front Cell Infect Microbiol. 2018;8. doi:10.3389/fcimb.2018.00376
12. Brives C, Pourraz J. Phage therapy as a potential solution in the fight against AMR: obstacles and possible futures. Palgrave Commun. 2020;6(1):1-11. doi:10.1057/s41599-020-0478-4
13. BiomX Announces Closing of the Acquisition of Adaptive Phage Therapeutics and Concurrent $50 Million Financing. BiomX, Inc. March 18, 2024. Accessed January 6, 2025. https://ir.biomx.com/news-events/press-releases/detail/103/biomx-announces-closing-of-the-acquisition-of-adaptive