Myriad applications of bacteriophages beyond phage therapy

Bacteriophages are the most abundant biological entity on the planet, likely surpassing bacteria by a factor of 10 (Mushegian, 2020). They play important roles in global ecology, biogeochemical cycles, and animal and plant health (Batinovic et al., 2019). Bacteriophages were discovered independently by Frederick Twort and Felix d'Herelle, and d'Herelle hypothesized that they were viruses as well as coined the term bacteriophage. d'Herelle also pioneered phage therapy, which is the utilization of phages to treat infections. From its beginning, phage therapy was very promising and useful for the treatment of dysentery, cholerae and other diseases, and its study and implementation continued to be carried out

This narrative review synthesizes evidence on diverse applications of bacteriophages beyond classical phage therapy. The literature discussed spans food safety and preservation (e.g., FDA-approved commercial phage products from Intralytix, Micros Food Safety, FINK TEC GmbH, Passport Food Safety Solutions, Phagelux) for controlling pathogens like Listeria monocytogenes, E. coli, Salmonella, Shigella, Campylobacter, Bacillus cereus, and others; environmental and clinical disinfection, particularly biofilm control with phage–chemical disinfectant synergy (sodium hypochlorite, benzalkonium chloride) against Pseudomonas aeruginosa and reports for S. aureus, E. coli, Acinetobacter baumannii, Klebsiella pneumoniae. The review covers phage-driven tradeoffs in bacteria where resistance to phages can reduce virulence or antibiotic resistance via mutations in receptors (flagella, type IV pili, capsule, efflux pumps, LPS), and inhibitory effects of filamentous phages on conjugation, with implications for limiting horizontal gene transfer. It highlights phage interference with quorum sensing, including a phage-encoded anti-activator (Aqs1) that inhibits LasR and PilB in P. aeruginosa. For microbiome modulation and dysbiosis management, the authors survey potential phage uses against Helicobacter pylori (favoring modulation over eradication), recurrent Clostridium difficile infection (as prophylaxis adjunct to or alternative to FMT), Cutibacterium acnes (including a topical phage gel trial), Gardnerella vaginalis in bacterial vaginosis, periodontal pathogens such as Streptococcus mutans and Aggregatibacter actinomycetemcomitans, and conceptual strategies to influence obesity-related microbiota. The review extends to nonbacterial diseases: phage proteins like M13 capsid GAIM that remodel amyloid aggregates in neurodegeneration; immunomodulatory and competitive receptor-binding roles of phages as adjuncts against viral infections (SARS-CoV-2, EBV), including TNF-α modulation by certain A. baumannii phages and KGD motifs on T4 capsid potentially interfering with coronavirus and EBV entry. Gene delivery use-cases include M13-based vectors delivering therapeutic genes (HSVtk) to glioblastoma via RGD4C-integrin targeting and prospects for phage-based CRISPR-Cas delivery to edit integrated viral genomes (HPV E6/E7). The review also examines pest control by targeting insect microbiomes (e.g., reducing Pseudomonas in Musca domestica gut; modulating Anopheles larvae microbiota with phages) and climate change mitigation by leveraging archaeal viruses to reduce methanogenic archaea in ruminants and using phages to influence bacterial populations related to CO2 fluxes. The authors discuss limitations, biosafety, ecological consequences, manufacturing, and scale-up challenges.

This is a narrative review. The authors compile and discuss published studies and reports on bacteriophage applications across food safety, clinical disinfection, microbiome modulation, antivirals and gene delivery, pest control, and climate mitigation, citing experimental and clinical examples to illustrate potential uses and challenges. No primary experimental methods are reported.

• Phages for food safety and preservation: Post-harvest and pre-packaging phage applications can reduce contamination by pathogens such as Listeria, E. coli, Salmonella, Shigella, Campylobacter, and others. Multiple commercial phage products have received FDA approval for specific uses. Potential targets also include Cronobacter sakazakii in infant formula and Clostridium botulinum in honey.
• Disinfection and biofilm control: Phage preparations, alone or combined with disinfectants (e.g., sodium hypochlorite, benzalkonium chloride), can synergistically eradicate biofilms of Pseudomonas aeruginosa. Effective phages have been reported against biofilms of S. aureus, E. coli, A. baumannii, and K. pneumoniae.
• Reducing antibiotic resistance and virulence: Bacterial resistance to phages often incurs fitness costs via mutations in phage receptors tied to virulence (flagella, type IV pili, capsule) or antibiotic resistance (efflux pumps, LPS), leading to attenuated virulence and resensitization to antibiotics (demonstrated in P. aeruginosa and A. baumannii). Filamentous phages (e.g., M13) can inhibit conjugation by occluding conjugative pili, potentially limiting spread of resistance genes. Phage-encoded proteins can inhibit quorum sensing (e.g., Aqs1 from P. aeruginosa phage DMS3 inhibits LasR and PilB with a 69-residue motif), reducing virulence factor expression.
• Treating dysbiosis and microbiome modulation: Phages could modulate rather than eradicate Helicobacter pylori; identify and deploy lytic phages against C. difficile for prophylaxis of recurrent diarrhea; utilize phages targeting Cutibacterium acnes (including a topical gel tested in a phase 1 cosmetic RCT) and Gardnerella vaginalis for acne and bacterial vaginosis; integrate phages with prebiotics/probiotics; deploy phages against periodontal pathogens (Streptococcus mutans, Aggregatibacter actinomycetemcomitans). Conceptually, targeting obesogenic bacteria with phages may aid in weight management.
• Nonbacterial disease applications: The M13 capsid GAIM motif binds/remodels amyloid aggregates, offering a novel approach for neurodegenerative diseases. Phages can exert antiviral adjunct effects (immunomodulation, competitive receptor binding) relevant to SARS-CoV-2 and EBV; certain A. baumannii phages (φkm18P, Bφ-R2096) reduce TNF-α in mouse pneumonia models. Engineered phage vectors (M13 with RGD4C targeting αvβ3) delivered HSVtk to glioblastoma in mice, with TMZ-inducible expression, showing efficacy and safety. Phage-based CRISPR-Cas delivery could target integrated viral genomes (e.g., HPV E6/E7) with potential advantages over eukaryotic viral vectors (specificity, cargo capacity, ease of engineering), though manufacturing and immunogenicity challenges remain.
• Pest control: Phage-mediated disruption of symbiotic microbiota can impair pests; e.g., up to 90% reduction of Pseudomonas aeruginosa in Musca domestica gut altered microbiome composition and development. In Anopheles larvae, adding phages targeting Enterobacter and Pseudomonas to water reduced survival and delayed development; combined phages showed synergy.
• Climate mitigation: Targeting methanogenic archaea with their viruses, or targeting bacterial partners that support methanogenesis, could reduce methane emissions from livestock; phages might also modulate bacterial populations affecting CO2 emissions and sequestration.
• Overall, phages offer versatile, renewable, and evolvable tools across industrial, medical, agricultural, and environmental contexts, with potential to alleviate antibiotic resistance, enhance food safety, manage microbiomes, support antiviral strategies, control pests, and mitigate greenhouse gases.

The review addresses the central question of how bacteriophages can be leveraged beyond classic antibacterial therapy. By aggregating evidence across domains, it shows that phages can serve as precise, self-amplifying biocontrol agents that complement or replace chemicals and antibiotics. In public health, phage use can improve food safety and hospital disinfection, and strategically selecting phages can drive evolutionary tradeoffs that reduce bacterial virulence and restore antibiotic susceptibility. In microbiome medicine, phages provide species- or strain-level tuning of community composition, offering alternatives to broad-spectrum antibiotics and fecal transplantation for certain dysbioses. In virology and oncology, phage components and engineered vectors expand therapeutic and diagnostic options, from amyloid modulation to targeted gene delivery and CRISPR-based antivirals. Agriculture benefits from phage-mediated manipulation of pest microbiota, potentially reducing reliance on pesticides. Environmentally, phage control of microbial processes offers new routes to mitigate methane and influence carbon cycling. The breadth of applications underscores phages’ relevance to tackling antibiotic resistance, improving patient outcomes, increasing food production, and addressing climate change. However, realizing these benefits requires careful consideration of ecological impacts, biosafety, manufacturing, regulatory pathways, and responsible stewardship to avoid repeating the pitfalls of antibiotic overuse.

Beyond classical phage therapy, bacteriophages have numerous promising applications across industry, medicine, veterinary practice, and environmental management. Potential contributions include: (1) mitigating the antibiotic resistance crisis by treating infections, reducing hospital and environmental reservoirs of multidrug-resistant bacteria through disinfection, and replacing or reducing antibiotic use in agriculture; even when resistance to phages emerges, new or engineered phages can be deployed, and resistance can entail reduced bacterial antibiotic resistance; (2) increasing food production and safety through control of bacterial plant pathogens and by weakening pest species dependent on microbiota; (3) improving human health by modulating microbiota, including potential reduction of obesity via targeting obesogenic bacteria; and (4) contributing to climate change mitigation by reducing methanogenic archaea or their bacterial partners in livestock. Continued innovation will likely uncover additional phage-based tools. To maximize benefits, it is essential to anticipate undesired effects, address scale-up and purification challenges, and develop robust safety and regulatory frameworks.

Most highlighted applications are at early stages and require substantial basic and translational research. There is a need to identify and characterize suitable lytic phages for targets such as Helicobacter pylori, Clostridioides difficile, and Gardnerella vaginalis, or to engineer temperate phages. Complex dysbioses (e.g., periodontal disease) involve multiple species in defined spatiotemporal successions, complicating phage therapy design. Phage-mediated lysis can release endotoxins (e.g., LPS) and other toxins, potentially provoking inflammation. Environmental phages can disrupt industrial fermentations (dairy), and phage-mediated horizontal gene transfer may disseminate antibiotic resistance genes; approaches like lysogenizing industrial strains to confer phage immunity may mitigate risks. A large fraction of phage genes have unknown functions, so cryptic deleterious genes cannot be fully ruled out. Ecological feedbacks may produce unintended consequences (e.g., selecting for more virulent quorum-sensing–proficient Pseudomonas). Finally, challenges in large-scale manufacturing, purification, standardization, and cost, along with the need for prudent, non-excessive use to avoid repeating antibiotic misuse, must be addressed.