Arms Race between Phages and Bacteria
Since bacteriophages were first identified in the early 1900s, scientists have described an ongoing ‘arms race’ between bacteria and phages. They don’t have nuclear weapons like humans, so what is the ‘arms race’ describing?
Red Queen Hypothesis
The bacteria-phage relationship is an example of the Red Queen hypothesis. In 1973, Leigh Van Valen proposed the idea that both phages and bacteria must and will continuously adapt to keep up with each other.
The name comes from Lewis Carroll’s Alice Through the Looking-Glass, where the Red Queen tells Alice: "Now, here, you see, it takes all the running you can do to keep in the same place." Van Valen proposed that species have to "run" i.e evolve, in order to stay in the same place or risk going extinct. Bacteria will evolve new ways to resist infection, and phages adapt to overcome those defences. [1]
Bacterial Phage Defence Mechanisms
Phages infect by binding to receptors on the surface and inject their genetic material into the bacteria. They hijack bacteria machinery to replicate and will rupture the bacteria to release the viral particles.
Bacteria utilise several tactics to try and defend themselves against the stages of phage replication.
Surface Receptor Modifications
To infect bacteria, phages must attach the surface via receptors. Phages use tail fibres or spikes that fit these receptors like a key in a lock. If the key (phage) doesn’t match the lock (receptor), it can’t attach. Bacteria can evolve by changing their locks (i.e. mutating their receptors), making it harder for phages to bind and infect them. [2]
Restriction-Modification System
Bacteria have special enzymes called restriction endonucleases, which act like molecular scissors to cut the invading viral DNA into pieces. Destroying the virus's genetic instructions prevents the virus from making more copies of itself, stopping the infection. [3]
CRISPR-Cas Systems
When bacteria survive a virus attack, small fragments of viral DNA are added to the bacteria’s genome within a CRISPR array. Imagine the DNA fragments as mugshots of a criminal (i.e the phage) and CRISPR as a filling cabinet, storing the information and keeping it safe.
The bacteria makes copies of the mugshot, known as crRNAs (CRISPR-RNAs) and these are distributed to Cas proteins, the immune security team of the bacteria. If the bacteria is re-infected with the same phage, the Cas proteins are able to recognise and destroy the viral DNA. [4]
Phage Counter-Strategies
In response to bacterial defences, phages have evolved mechanisms to overcome these barriers.
Mutational Escape
Phages have a high mutation rate, which means they can quickly change their DNA. When bacteria evolve to block the phages, the phages can mutate these binding proteins to fit, either new or altered receptors on the bacteria. [5]
Phage DNA Modification
Phages can disguise their DNA by adding special chemical changes, like the addition of sugar molecules (glycosylation) or addition of CH3 (methylation). This makes it harder for bacteria to recognize and destroy the DNA. [6]
Anti-CRISPR Proteins
Some phages can produce anti-CRISPR proteins that block the CRISPR-Cas immune response of certain bacteria. [7]
The ongoing arms race between phages and bacteria offers valuable insights into microbial evolution and has significant implications for phage therapy. As AMR become a prevalent societal issue, phages provide a potential solution by targeting specific bacteria without promoting resistance. Understanding phage strategies, like mutational escape and CRISPR-Cas, can enhance the development of tailored treatments against antibiotic resistant bacteria. [8]
References
1. Brockhurst, M.A., Chapman, T., King, K.C., Mank, J.E., Paterson, S. and Hurst, G.D.D. (2014). Running with the Red Queen: the Role of Biotic Conflicts in Evolution. Proceedings of the Royal Society B: Biological Sciences, [online] 281(1797), p.20141382. doi: https://doi.org/10.1098/rspb.2014.1382.
2. E Egido, J., Rita Costa, A., Aparicio-Maldonado, C., Haas, P.-J. and Brouns, S.J.J. (2025). Mechanisms and Clinical Importance of Bacteriophage Resistance. FEMS Microbiology Reviews, 46(1). doi: https://doi.org/10.1093/femsre/fuab048.
3. Shi, K., Oakland, J.T., Kurniawan, F., Moeller, N.H., Banerjee, S. and Aihara, H. (2020). Structural basis of superinfection exclusion by bacteriophage T4 Spackle. Communications Biology, [online] 3(1), pp.1–8. doi: https://doi.org/10.1038/s42003-020-01412-3.
4. Koonin, E.V., Makarova, K.S. and Zhang, F. (2025). Diversity, Classification and Evolution of CRISPR-Cas Systems. Current Opinion in Microbiology, 37, pp.67–78. doi: https://doi.org/10.1016/j.mib.2017.05.008.
5. Laanto, E., Mäkelä, K., Hoikkala, V., Ravantti, J.J. and Sundberg, L.-R. (2020). Adapting a Phage to Combat Phage Resistance. Antibiotics, 9(6), p.291. doi: https://doi.org/10.3390/antibiotics9060291.
6. Vasu, K. and Nagaraja, V. (2013). Diverse Functions of Restriction-Modification Systems in Addition to Cellular Defense. Microbiology and Molecular Biology Reviews, 77(1), pp.53–72. doi: https://doi.org/10.1128/mmbr.00044-12.
7. Hampton, H.G., Watson, B.N.J. and Fineran, P.C. (2020). The Arms Race between Bacteria and Their Phage Foes. Nature, [online] 577(7790), pp.327–336. doi: https://doi.org/10.1038/s41586-019-1894-8.
8. Teklemariam, A.D., Al-Hindi, R.R., Qadri, I., Alharbi, M.G., Ramadan, W.S., Ayubu, J., Al-Hejin, A.M., Hakim, R.F., Hakim, F.F., Hakim, R.F., Alseraihi, L.I., Alamri, T. and Harakeh, S. (2023). The Battle between Bacteria and Bacteriophages: A Conundrum to Their Immune System. Antibiotics (Basel, Switzerland), [online] 12(2), p.381. doi: https://doi.org/10.3390/antibiotics12020381
The information and opinions expressed in this blog post represent those of the original author of the blog. They do not necessarily reflect and represent the views and opinions of the Phage Collection Project or its staff.