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).

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.

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