Guest writer Professor Martha Clokie of the University of Leicester explores the novel topic of Phage Therapy.
It is predicted that by the year 2050, more people will die from antibiotic resistant bacterial infections than from cancer. Indeed, antibiotic resistance threatens to undermine modern medicine as we know it because effective antibiotics underpin all other forms of medicine including chemotherapy, caesarean sections and other routine operations.
Bacteriophages, abbreviated as phages, are viruses that infect and kill bacteria, leaving human cells unharmed. They were discovered decades before antibiotics, and were used extensively to treat infections in humans in a practice known as phage therapy. After antibiotics were developed, phages were considered to be too specific and complicated and therefore in most parts of the world their use as antimicrobials stopped2.
Although phages were used extensively in the former USSR and in some European countries, they have not been tested under modern clinical trial conditions or used within standard European or American regulatory frameworks3.
Being the natural enemies of bacteria, phages have evolved with their bacterial hosts and can be found in nature wherever the bacteria they infect exist4. Phages can also effectively kill bacteria that are resistant to multiple antibiotics. To use and develop phages as antimicrobials we need to isolate them, then learn how to use and formulate them to target specific infections and carry out suitable trials to meet necessary regulatory requirements3.
There are a staggering 1031 phages on Earth which is more than there are of any other biological entity4. If you were to line them up head to tail they’d span our galaxy a thousand times!
Most of the phages that have been characterized, have double-stranded DNA genomes, often fairly hefty – encoding around 50 – 250 genes. These double stranded DNA genomes are encased in a protective protein coat and have tail fibres that determine which bacterial species to infect.
When phages are used topically, nebulised into the lungs or taken orally they do not cause a strong immune response5.
Novel Potential Treasure Troves
The genomes of phages are incredibly diverse, with completely novel and unrecognizable genomes still frequently identified in new phages6. We can therefore think of phages as novel treasure troves of antibiotics that, if developed properly, could support the treatment of human infection caused by drug resistant bacteria.
Phages are generally specific to their bacterial species, or even just to one or a few subspecies of bacteria. This same specificity that prevented them from being developed in the 1940s is now considered to be an advantage because phages will treat the bacterial infection but leave the rest of the human microbiota in place to carry out their useful functions.
It is much easier to find bacteriophages for some bacterial species than others. Fortunately, many phages have been found for some of the most problematic multidrug resistant bacteria such as the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa and Enterococcus spp.). Plus, phages have also been found and sometimes engineered for other serious pathogens such as M. tuberculosis (TB) and related atypical mycobacterial species that cause lung diseases7.
Although bacteria can and will develop resistance to phages there are multiple strategies that can be used to minimize this problem. These include the use of phage combinations or ‘cocktails’2. Furthermore, to avoid phage predation, bacteria often need to undergo fairly serious mutations and this tends to leave them less well adapted to behave as disease-causing bacteria. In some cases phages can work synergistically with antibiotics so to withstand phage attack, the bacteria lose their antibiotic resistance mechanisms8. The combination of specific phages with antibiotics can also be used together to reduce the effective antibiotic dose, and in some cases completely restore antibiotic sensitivity to bacteria3,8.
There are still areas that need further clarity if phages are to become treatments of choice in the future. Phages break many antimicrobial ‘norms’; they are difficult to regulate (as they are organisms rather than compounds) and as a result of this they can evolve in short timescales. The fact that they are naturally occurring and that novel inventive steps can be hard to define, makes phages difficult to patent and therefore protect to give companies the intellectual protection they need to fund commercial development.
Clinical trial data is clearly needed for phage therapy to become mainstream. There are currently several clinical trials planned worldwide, as interest in phage therapy is increasing in response to the need to develop alternative antimicrobials9. Evidence for the renewed interest in phages can be seen from engagement and funding with the pharmaceutical industry and within clinical and academic circles, all of whom have a combined common objective to unlock the potential of this somewhat forgotten treasure trove, in order to maintain and even improve the future of medical support to patients affected by bacterial infections.
- Abedon ST, Kuhl SJ, Blasdel BG, Kutter EM. Phage treatment of human infections. Bacteriophage. 2011 Mar;1(2):66-85. doi: 10.4161/bact.1.2.15845. PMID: 22334863; PMCID: PMC3278644.
- Gordillo Altamirano FL, Barr JJ. Phage Therapy in the Postantibiotic Era. Clin Microbiol Rev. 2019 Jan 16;32(2):e00066-18. doi: 10.1128/CMR.00066-18. PMID: 30651225; PMCID: PMC6431132.
- Clokie MR, Millard AD, Letarov AV, Heaphy S. Phages in nature. Bacteriophage. 2011;1(1):31-45. doi:10.4161/bact.1.1.14942
- Chang RYK, Wallin M, Lin Y, et al. Phage therapy for respiratory infections. Adv Drug Deliv Rev. 2018;133:76-86. doi:10.1016/j.addr.2018.08.001
- Al-Shayeb B, Sachdeva R, Chen LX, Ward F, Munk P, Devoto A, Castelle CJ, Olm MR, Bouma-Gregson K, Amano Y, He C, Méheust R, Brooks B, Thomas A, Lavy A, Matheus-Carnevali P, Sun C, Goltsman DSA, Borton MA, Sharrar A, Jaffe AL, Nelson TC, Kantor R, Keren R, Lane KR, Farag IF, Lei S, Finstad K, Amundson R, Anantharaman K, Zhou J, Probst AJ, Power ME, Tringe SG, Li WJ, Wrighton K, Harrison S, Morowitz M, Relman DA, Doudna JA, Lehours AC, Warren L, Cate JHD, Santini JM, Banfield JF. Clades of huge phages from across Earth's ecosystems. Nature. 2020 Feb;578(7795):425-431. doi: 10.1038/s41586-020-2007-4. Epub 2020 Feb 12. PMID: 32051592; PMCID: PMC7162821.
- Dedrick RM, Guerrero-Bustamante CA, Garlena RA, et al. Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus. Nat Med. 2019;25(5):730-733. doi:10.1038/s41591-019-0437-z
- Chan BK, Sistrom M, Wertz JE, Kortright KE, Narayan D, Turner PE. Phage selection restores antibiotic sensitivity in MDR Pseudomonas aeruginosa. Sci Rep. 2016;6:26717. Published 2016 May 26. doi:10.1038/srep26717
- Górski A, Borysowski J, Międzybrodzki R. Phage Therapy: Towards a Successful Clinical Trial. Antibiotics (Basel). 2020;9(11):827. Published 2020 Nov 19. doi:10.3390/antibiotics9110827
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