Phage Therapy: A Renewed Approach to Combat Antibiotic-Resistant Bacteria

AbstractThe evolution of antibiotic resistant bacteria threatens to become the leading cause of worldwide mortality. This crisis has renewed interest in the practice of phage therapy. Yet, bacteria’s capacity to evolve resistance is likely to debilitate this therapy as well. To combat the evolution of phage resistance and improve treatment outcomes, many have suggested leveraging phages’ ability to counter resistance by evolving phages on target hosts before using them in therapy (phage training). We found that during in vitro experiments, a phage trained for 28 days suppressed bacteria ∼1000-fold for 3-8 times longer than its untrained ancestor. This extension was due to a delay in the evolution of resistance. Several factors contributed to this prolonged suppression. Mutations that confer resistance to trained phages are ∼100× less common and, while the target bacterium can evolve complete resistance to the untrained phage in a single step, multiple mutations are required to evolve complete resistance to trained phages. Mutations that confer resistance to trained phages are more costly than mutations for untrained phage resistance. And when resistance does evolve, trained phages are better able to suppress these forms of resistance. One way the trained phage improved was through recombination with a gene in a defunct prophage in the host genome, which doubled phage fitness. This direct transfer of information encoded by the host but originating from a relict phage provides a previously unconsidered mode of training phage. Overall, we provide a case study for successful phage training and uncover mechanisms underlying its efficacy.Significance StatementThe evolution of antibiotic resistant bacteria threatens to claim over 10 million lives annually by 2050. This crisis has renewed interest in phage therapy, the use of bacterial viruses to treat infections. A major barrier to successful phage therapy is that bacteria readily evolve phage resistance. One idea proposed to combat resistance is “training” phages by using their natural capacity to evolve to counter resistance. Here, we show that training phages by coevolving them with their host for one month enhanced their capacity for suppressing bacterial growth and delayed the emergence of resistance. Enhanced suppression was caused by several mechanisms, suggesting that the coevolutionary training protocol produces a robust therapeutic that employs complementary modes of action.

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Phage therapy for antibiotic resistant bacteria

Pathology ◽

10.1016/j.pathol.2020.01.180 ◽

2020 ◽

Vol 52 ◽

pp. S52

Author(s):

Jonathan Ripley Iredell

Keyword(s):

Phage Therapy ◽

Resistant Bacteria ◽

Antibiotic Resistant Bacteria ◽

Antibiotic Resistant

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Phage Therapy: A Potential Solution for Antibiotic Resistance

10.51627/pghr.2021.08.00071 ◽

2021 ◽

Author(s):

Chirag Choudhary ◽

Keyword(s):

Antibiotic Resistance ◽

Bacterial Infections ◽

Phage Therapy ◽

Biological Agents ◽

Resistant Bacteria ◽

Potential Solution ◽

Antibiotic Resistant Bacteria ◽

Antibiotic Resistant ◽

The Future

The idea of using a virus to kill bacteria may seem counterintuitive, but it may be the future of treating bacterial infections. Before the COVID-19 pandemic, one of the most frightening biological agents were so-called “superbugs” – antibiotic resistant bacteria – which could not be treated with conventional therapeutics. When antibiotics were first developed, they were hailed as a panacea. A panacea they were not.

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Editorial for the Special Issue: “Phage Therapy: A Biological Approach to Treatment of Bacterial Infections”

Antibiotics ◽

10.3390/antibiotics9100721 ◽

2020 ◽

Vol 9 (10) ◽

pp. 721

Author(s):

Saija Kiljunen

Keyword(s):

Healthcare Costs ◽

Bacterial Infections ◽

Phage Therapy ◽

Resistant Bacteria ◽

Special Issue ◽

Antibiotic Resistant Bacteria ◽

Antibiotic Resistant ◽

Biological Approach

The emergence of antibiotic-resistant bacteria presents a major challenge in terms of increased morbidity, mortality, and healthcare costs [...]

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Phage Therapy Is Effective in a Mouse Model of Bacterial Equine Keratitis

Applied and Environmental Microbiology ◽

10.1128/aem.01166-16 ◽

2016 ◽

Vol 82 (17) ◽

pp. 5332-5339 ◽

Cited By ~ 13

Author(s):

Takaaki Furusawa ◽

Hidetomo Iwano ◽

Yutaro Hiyashimizu ◽

Kazuki Matsubara ◽

Hidetoshi Higuchi ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Mouse Model ◽

Phage Therapy ◽

Host Cells ◽

Resistant Bacteria ◽

Broad Host Range ◽

Bacterial Keratitis ◽

Antibiotic Resistant Bacteria ◽

Antibiotic Resistant ◽

Content Type

ABSTRACTBacterial keratitis of the horse is mainly caused by staphylococci, streptococci, and pseudomonads. Of these bacteria,Pseudomonas aeruginosasometimes causes rapid corneal corruption and, in some cases, blindness. Antimicrobial resistance can make treatment very difficult. Therefore, new strategies to control bacterial infection are required. A bacteriophage (phage) is a virus that specifically infects and kills bacteria. Since phage often can lyse antibiotic-resistant bacteria because the killing mechanism is different, we examined the use of phage to treat horse bacterial keratitis. We isolatedMyoviridaeorPodoviridaephages, which together have a broad host range. They adsorb efficiently to host bacteria; more than 80% of the ΦR18 phage were adsorbed to host cells after 30 s. In our keratitis mouse model, the administration of phage within 3 h also could kill bacteria and suppress keratitis. A phage multiplicity of infection of 100 times the host bacterial number could kill host bacteria effectively. A cocktail of two phages suppressed bacteria in the keratitis model mouse. These data demonstrated that the phages in this study could completely prevent the keratitis caused byP. aeruginosain a keratitis mouse model. Furthermore, these results suggest that phage may be a more effective prophylaxis for horse keratitis than the current preventive use of antibiotics. Such treatment may reduce the use of antibiotics and therefore antibiotic resistance. Further studies are required to assess phage therapy as a candidate for treatment of horse keratitis.IMPORTANCEAntibiotic-resistant bacteria are emerging all over the world. Bacteriophages have great potential for resolution of this problem. A bacteriophage, or phage, is a virus that infects bacteria specifically. As a novel therapeutic strategy against racehorse keratitis caused byPseudomonas aeruginosa, we propose the application of phages for treatment. Phages isolated in this work hadin vitroeffectiveness for a broad range ofP. aeruginosastrains. Indeed, a great reduction of bacterial proliferation was shown in phage therapy for mouse models ofP. aeruginosakeratitis. Therefore, to reduce antibiotic usage, phage therapy should be investigated and developed further.

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