by Veerasak “Jeep” Srisuknimit
figures by Jovana Andrejevic

Our time with antibiotics is running out. In 2016, a woman in Nevada died from a bacterial infection caused by Klebsiella pneumoniae that was resistant to all available antibiotics. Bacteria that is resistant to colistin, an antibiotic of last resort, has been discovered on pig farms in China. Bacteria have been evolving to resist antibiotics faster than ever.

Meanwhile, it takes scientists ten or more years to develop a new antibiotic and get FDA approval. Our slow response means that we are losing in this antibiotic arms race. We urgently need an alternative method to fight bacterial infection. One promising method for killing bacteria is to use bacteriophages: viruses that infect and kill bacteria.

Bacteriophages: Natural enemies of bacteria

Bacteriophages, called phages for short, were discovered independently by Frederick Twort in 1915 and Félix d’Herelle in 1917, over a decade before penicillin, the most well known antibiotic. In the following years, phages were employed to treat dysentery and cholera with success. These phages were isolated from the stool of patients who unexpectedly recovered from the illness. Scientists speculated that there was something in these lucky patients that helped to remove harmful bacteria from their guts. They isolated phages from the stools, purified them, and gave the phages to other patients. In one study, 63% of untreated people suffering from cholera in Punjab, India died while only 8% of those who were treated by phages died. Despite the early success, phages therapy was eclipsed by the discovery of penicillin and the rise of antibiotics.

At the time phages were initially used for treatment of cholera, scientists had only just begun to study viruses and speculate about how phages work. It was not until 1940 that the first images of phages were obtained using an electron microscope. We now know that phages are viruses that infect only bacteria. As a type of virus, phages cannot live and reproduce alone. Viruses need to invade a host cell, consume the host’s nutrients to make more copies of themselves, and lastly get out of the host cell – often by killing the host in the process.

In general, phages start their killing first by recognizing and landing on a bacteria. Each type of phages has a specific landing pad. The phage then injects its DNA into the bacteria. This DNA copies itself, makes more of the phage’s shell, and packages the newly made DNA into the new shell. Lastly, the phage produces toxic chemicals that rupture the bacterial host from inside out, releasing its newly made children to the outside to infect even more bacteria (Figure 1).

Figure 1: How phage kills bacteria. (1) Phage first lands on bacteria. (2) It then injects its DNA inside bacteria. (3) The DNA is copied and is used to make packaging for a new generation of phages. (4) Lastly, the new phages assemble and burst of bacteria, killing it in the process.

Advantages of Phages over Antibiotics

An antibiotic is a chemical that kills bacteria. It does so by disrupting one or more of the important processes that bacteria need to survive. Because these processes are common in many bacteria, one “broad spectrum” antibiotic could potentially kill many species of bacteria at once. While antibiotics have revolutionized medicine and are often very effective in stopping bacterial infection, well-developed phages could have several advantages over antibiotics.

First, phages are specific to one species of bacteria and are therefore unlikely to disturb beneficial microbe living in our guts. The human body is populated by over a thousand species of microbes, which are estimated to make up about 3-5 pounds of our total body weight. These microbes do important jobs for us, such as helping us make nutrients we cannot make ourselves. Because many antibiotics kill bacteria indiscriminately, treating an infection with an antibiotic results also in killing this beneficial gut bacteria. Each phage, on the other hand, evolved to kill just a specific set of bacteria. Because phage kills with a narrow scope, it could be used to cure an infection without disturbing the community of beneficial bacteria in our body.

Second, phages are able to kill antibiotic-resistant bacteria. The way that phages kill bacteria is harder for bacteria to develop resistance against compared to the way that antibiotics kill bacteria. Rather than stopping bacteria from doing one specific process like in the case of antibiotics, phages actively destroy the bacteria’s cell wall and cell membrane and kill bacteria by making many holes from the inside out. In addition, many bacteria develop biofilm – a thick layer of viscous materials that protect them from antibiotics. Many phages are equipped with tools that can digest this biofilm.

Why Aren’t Phages Used?

With the exception of treatment options available in a few countries, phages have been largely abandoned as a treatment for bacterial infection. One main reason is because antibiotics have been working well enough over the past 50 years that most countries have not re-initiated a study on the clinical uses of phages. But another reason is that there are some limitations for using phages as a treatment.

First, phages are more difficult to prepare cleanly. To produce phages, first scientists have to grow a large quantity of bacteria that is the natural host of the phage. The bacteria is then infected with the phages, and the phages in turn reproduce and kill all the bacteria. The difficulty begins with the isolation of live phages from a multitude of dead bacteria corpses. If not removed from the final medication given to the patient, dead bacteria bodies could trigger a deadly immune response called sepsis. Another challenge is to obtain the right concentration of phages since its concentration can’t be measured directly. If the concentration is too low, phage therapy would inefficacious. Many of the early commercial phage products were of poor quality and incapable of treating infectious disease, leading to phage therapy being discredited.

Second, phage takes a longer time to employ in a treatment compared to antibiotics. Because a single type of phage can only infect a few species of bacteria, phage selection has to be done with care. First, doctors have to figure out the identity of bacteria that is causing the illness. Then they have to check whether the available phages could kill this strain of bacteria. If not, they have to search for new phages that could do the job. This process takes time that the patients may not have – especially when phages are used only as a last resort on very ill patients. On the other hand, because antibiotics kill indiscriminately, doctors can prescribe an antibiotic to treat a patient without needing to first identify the specific type of bacteria.

Other concerns about phage therapy are centered on its safety and efficacy. Because the western world abandoned phage therapy many decades ago, there is little data about these topics available. However, research on phage therapy continues and prospers in France and eastern European countries, especially in Georgia. From their studies, phage therapy does not exhibit any major safety concerns.

Figure 2: Phages can be used in two ways: to protect or to cure. Here are two examples. Phages can be used burned victims to protect their skins from bacterial infection. Phage can also be used to treat a patient that is overwhelmed by antibiotic-resistant bacterial infection.

Where Are We Now?

Now that more and more bacteria have developed resistance to antibiotics, scientists around the world have a renewed interests in phages. The European Union invested 5 millions euros in Phagoburn, a project that studies the use of phages to prevent skin infections in burn victims (Figure 2). In the USA, the FDA approved ListshieldTM, a food additive containing phages, that kills Listeria monocytogenes, one of the most virulent foodborne pathogens and one cause of meningitis. Currently, many clinical trials using phage to treat or prevent bacterial infections such tuberculosis and MRSA are undergoing.

Despite the fact that phage therapy is not yet approved by FDA, phages have already been used to save lives in experimental treatments. A miraculous recovery of a patient who suffered from antibiotic-resistant bacteria was reported in San Diego. While on a vacation in Egypt, Tom Patterson was infected by a multidrug-resistant strain of Acinetobacter baumannii. He was flown back to California and treated with antibiotics for over 100 days, but Patterson did not get better and fell into coma. He was finally saved by a cocktail of phages purified from sewage in Texas.

In the near future, as antibiotics lose their effectiveness, we may begin to hear more stories like this. And one day, phage might move from our last resort against antibiotic-resistant bacteria to our first line of defense.

Veerasak “Jeep” Srisuknimit is a fifth-year Ph.D. student in the department of Chemistry and Chemical Biology at Harvard University.

For more information:

Perspective article: https://www.nature.com/articles/nrmicro3564

35 thoughts on “Bacteriophage: A solution to our antibiotics problem?

  1. Thanks for this perfect text. I am Ph.D student in bacteriology and my thesis is about phage therapy in burn wound infections. I really interested in phage therapy and I hope to do my best in my own thesis.

  2. A very successful laboratory in the eastern block had isolated phages that were able to treat almost all bacterial infections. When the eastern block dismantled, the laboratory opened all its secrets in the hope that the research could continue. with foreign investment.
    However no one was interested primaraly because the Drugs companies could not make any money out of it .
    It is scandalous that many have died, who could have been succesfully treated with phages, because because of the Wests money orientated drugs culture.
    For those who have untreatable bacterial infections , many can be treated by the instute in Georgia where research continues, Why can they not be treated here in the UK?

    1. A lot of research is needed in order to ensure the safety of phage treatments. I agree with you that research on phages should be sped up. Perhaps countries as Belgium, Germany, the UK and the Netherlands should cooperate to work towards a solution more effectively.

    2. Can you tell more about the facility or history of this lab, and where the research can be obtained? I heard there are in fact phage “drugs” in use in the Eastern Block. But I can’t find the company or location.

  3. I lost two family members to MRSA, both my father and my mother-in-law whom I was a caregiver for. This research is needed.

  4. I lost my father because of pnemoniae , antibiotic made him feel slighlty okey. and he went back to his infected status . and no second coarse of antibiotic could have been given. he passed away with in few days .
    i would like to see research speed up on this . beacuse they are many cases in the whole world that antibiotic is resistant and patients are dying .

  5. Am I the only 12 year old here? This is a very intriguing subject though…. Quite interesting, very neat like quantum mechanics and a real world threat.

  6. Investigation to development of bacteriophage to specifically attack P. gingivalis bacteria
    associated with gingivitis and a possible link to Alzheimer disease.

    1. Many reputable science materials suppliers sell plaque assays from which you can purify your own batch of phages. Make sure you research which bacterial strain corresponds to it before you purchase the phage however, as they are highly specific killers as mentioned in the article. Here are a few sites to hit:

      https://www.carolina.com

      http://www.cellexus.com (I haven’t tried this, but it appears to have a “bioreactor” that makes purification of the plaque assay much easier and with less chance of contamination. Do your own research here though)

      http://www.gibsonbioscience.com/

      These are the ones I could find quickly, but I’m sure there are more. Good luck!

  7. How would someone in the Uk get the correct phage for an infection? Angela Rippon reported on phages on a shocking TV program this week about antibiotic resistance. It would be so useful to be able to have a link to a lab in Georgia or elsewhere in Eastern Europe where the work is done. One interviewer had been receiving the phages from Georgia for years.

      1. Wrong, viruses CAN work on eukaryotic cells as that is how viral infections like influenza work. I am unsure if it can cure cancer though because even if a virus was developed to target cancer, it may attack your good cells as well because they share the same genetic info. This is very interesting though and needs some research done on it.

        1. Yes, viruses in general can affect eukaryotic cells, but this whole article is about bacteriophages literally meaning bacteria-eaters. Bacteriophages target ONLY prokaryotic cells such as bacteria.

  8. I believe if some FOI questions asked to find out those who have lost lives & limbs from sepsis & hospital acquired infections & infections .This may speed up the process.Petitions too Change – Momentum may help .I have put forward Proposals for Research NIH via the Charities but feel too bothered about funding themselves as no replies .This would be a good cause for bio detection dogs/ medical assistance to take up.

  9. Cystic fibrosis patients live everyday taking antibiotics with no alternative therapy.They have several bacterial infections in one patient. Surely they would be prime candidates for phage therapy research.For Gods sake , hurry up with the science.They have never ending supplies of thick sticky mucous to experiment with.Get on with it.

  10. Hello I am a 62 year old mother and grandmother I had my first complete knee surgery replacement in October 2018 and have had 2 more surgery’s since I contracted a bacterial infection on my 2 knee surgery in November 2018 as of this date it is still with me. I now have to look forward to a 4th surgery to “clean out my knee ” and reattach my knee cap again if possible depending on the damage that has been done by the infection. I am scared to death of loosing my leg if this bacterial infection is not controlled. I was on a 8 week regime of Vancomycin through a pick line it did not help. My Dr. has since switched me over to Doxycycline no luck yet. I am wondering the status of phage treatment and if it is even possible I live in the US in Seattle WA.
    Thank you

    1. I don’t know ma’am. I am sorry to hear of your situation and would love to help. But I am just a lowly high school student with no college education. I would think there would be treatment options involving phages for your infection, especially of an infection of your caliber. Hope you get the treatment you need ma’am. Good luck. P.S. Respond if you get better.

  11. Whats the point removing dead bacteria bodies before injecting phages into the body?
    There would be dead bacteria bodies anyways if the phage kills bacterium inside the body. Would that not also cause sepsis

  12. I would like to if, phage therapy could be expanded on. Just in the oceans, 40% of bacteria get killed. Also, how would the sepsis work? If Sepsis is dead bacteria, then how would the bits of dead bacteria in our body do to us?

  13. I have mycobacterium progressively eating cavities in my lung (9mm sized) , I am relatively young and otherwise healthy, but I am told antibiotics are not likely to work, I had recently had a washing of my lungs to get an accurate diagnosis of the strain of bacteria. I am keen to know more about Phages.

  14. I have known about Phages for years and was very disappointed they are not available to many antibiotic sufferers for last resort treatment. Many people have died needlessly without the chance of being treated by this safe bacteria. Long ago it was used on people who were infected with Cholera… It is a safe method to fight antibiotic resistance but it takes a bit longer to use and not as easy as a pill to swallow but that is OK if your loved one does not die.

  15. One issue that has been left unsaid is that phages do in fact mutate. The same as bacteria do and that is the very reason a bacteria can become immune to an antibiotic. But the thing left unsaid is that the FDA has approved the use of phages being sprayed on foods. So most fruits and vegetables now days are sprayed with phages before shipped to market. The reason is the phages kill bacteria on the food which makes the food last longer in travel and storage so there is less food rot. This sounds good but the down side is you end up eating the food which has phages on it and the phages end up in your gut. Then the phages kill your gut flora and that I would assume leads to all kinds of IBS problems. They even spray phages on organic foods now as well. I dont say this to cause a panic but there should be some concern I would think given the nature of phages and bacteria to mutate. And one has to wonder did humans have all the kinds of IBS and gut problems long ago that they have now, or could some of these problems be all because the foods we are eating, that are sprayed now with phages, are putting phages in out gut that maybe normally would not be there.

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