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After the fall of antibiotics… how can phage therapy fight drug-resistant infections?

PLOS Your Say

Antibiotics have been an enormously effective weapon for treating bacterial infections and saving millions of lifes, but phage therapy is now advancing as an alternative to them in the face of the emergence of resistant bacteria.

Unfortunately, our society lives in an era where the use and abuse of antibiotics is generating more and more drug-resistant bacteria. This resistance complicates the search for an effective treatment to fight infection, to the extent that some diseases that were once considered mild can now be fatal. During 2019, more than 1.2 million deaths from drug-resistant infections were recorded, and the World Health Organization (WHO) estimates that the number could rise to 10 million per year by 2050. This threat to global public health is known as the post-antibiotic era and the search for alternative treatments, such as bacteriophages (or phages for short), is urgently needed.

Phages are viruses that uniquely and specifically infect bacteria. Like other viruses, they introduce their genetic material into the cell they parasitise and sometimes multiply it to generate more viruses, which will destroy the cell to free themselves and spread to find others to infect. This is why phage therapy is known as the use of phages to treat bacterial infections. Interestingly, phage therapy existed before Alexander Fleming discovered penicillin, but antibiotics quickly eclipsed its prominence and became the choice that revolutionised the field of medicine. It is not surprising that interest in phage therapy has returned in recent decades, as it is a strategy that targets the desired bacteria without affecting other beneficial microbes living on different surfaces of the body. However, like any other treatment, it has its shortcomings. Phages are still “foreign bodies” to our immune system when they reach the bloodstream, and although they are not intended to harm us, they are eventually eliminated by our defences. Furthermore, it has been found that bacteria may also become resistant to phages over time, so… does this mean that phage therapy is not a solution, that we are back to square one?

Fortunately the answer is no, there is still hope for phage therapy. Among the solutions being proposed, one of them is based on combining phages with antibiotics. Although this may seem unhelpful, it has been shown that when bacteria develop resistance to one treatment, they may become vulnerable to the other one. Another solution being studied is the use of viral endolysins, proteins produced by phages during infection to destroy the bacterial wall, kill the cell and then break free and spread outwards. Administering endolysins instead of phages would allow a rapid and targeted attack on bacteria without some of the problems that characterise classical phage therapy, including the dreaded development of resistance. Since endolysins target sensitive components of the bacterial wall, bacteria are unlikely to modify them to resist treatment.

Changing the dramatic future that antibiotic resistance has in store for our society is no simple task. But it will require major changes in the therapies we use and greater accessibility of them worldwide.

References

  1. Pires DP, Martins Costa AR, Pinto G, Meneses L, Azeredo J. Current challenges and future
    opportunities of phage therapy. FEMS Microbiol Rev. 2020 Nov;44(6):684-700.
  2. Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance
    in 2019: a systematic analysis. Lancet. 2022 Feb 12;399(10325):629-655. doi:
    10.1016/S0140-6736(21)02724-0.
  3. Pires DP, Martins Costa AR, Pinto G, Meneses L, Azeredo J. Current challenges and future
    opportunities of phage therapy. FEMS Microbiol Rev. 2020 Nov;44(6):684-700.
  4. Luong T, Salabarria AC, Roach DR. Phage therapy in the resistance era: where do we stand
    and where are we going? Clin Ther. 2020 Sep;42(9):1659-1680. doi:
    10.1016/j.clinthera.2020.07.014.
  5. Oechslin F. Resistance Development to Bacteriophages Occurring during Bacteriophage
    Therapy. Viruses. 2018 Jun 30;10(7):351. doi: 10.3390/v10070351.
  6. Ong SP, Azam AH, Sasahara T, Miyanaga K, Tanji Y. Characterization of Pseudomonas lytic
    phages and their application as a cocktail with antibiotics in controlling Pseudomonas
    aeruginosa. J Biosci Bioeng. 2020 Jun;129(6):693-699. doi: 10.1016/j.jbiosc.2020.02.001.
  7. Berryhill BA, Huseby DL, McCall IC, Hughes D, Levin BR. Evaluating the potential efficacy
    and limitations of a phage for joint antibiotic and phage therapy of Staphylococcus aureus
    infections. Proc Natl Acad Sci USA. 2021 Mar 9;118(10):e2008007118.
  8. Murray E, Draper LA, Ross RP, Hill C. The advantages and challenges of using endolysins in
    a clinical setting. Viruses. 2021 Apr 15;13(4):680. doi: 10.3390/v13040680.
  9. Mondal SI, Akter A, Draper LA, Ross RP, Hill C. Characterization of an endolysin targeting
    Clostridioides difficile that affects spore outgrowth. Int J Mol Sci. 2021 May
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Author information:
Alejandro Fernández Llorente is a master’s student at Universidad Autónoma de Madrid,
Spain. His current studies focus on the generation and optimisation of recombinant poxviruses
as vaccine vectors against several high-impact human diseases.

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