Bacteriophages, Phage Therapy, and Antibiotic Resistance
Antibiotic Resistance: A Serious Problem
The discovery of antibiotics and their ability to kill bacteria was an exciting development in human history. For a while, antibiotics were a wonder cure for bacterial infections. They saved a multitude of lives and relieved misery and discomfort. Antibiotics are still useful today, but an increasing number of bacteria are becoming resistant to these drugs.
Antibiotic resistance is a very serious problem. New ways to fight bacteria are needed in order to treat the infections that threaten our lives and our health. Phage therapy—the use of specific viruses to fight dangerous bacteria—may be one solution to this dilemma.
What Is Phage Therapy?
A bacteriophage, or phage, is a virus that attacks bacteria. During the attack, the phage sends its genetic information into a bacterial cell and "forces" the cell to make new virus particles. The virus particles are released as the bacterial cell bursts and can then infect new cells. The phage infection kills the bacterium.
Each type of phage attacks a specific strain of bacteria, but it doesn't attack human cells or other types of bacteria. Therefore bacteriophages could be used as therapeutic agents inside our bodies. This process is actually happening in countries that were once part of the Soviet Union and is known as phage therapy. The therapy has been used for many years in some parts of the world, with apparent success. Now western scientists are studying the effectiveness and safety of phage therapy.
How Does Antibiotic Resistance Develop?
The genes of a bacterium or a human are part of a molecule known as DNA, or deoxyribonucleic acid. Genes give bacteria their characteristics. Although the members of one species of bacteria are very similar to each other genetically, they aren't identical. Bacteria pick up new genes (or gene variants) and bits of DNA from other bacteria. They also develop new characteristics due to mutations, which are changes in the structure of a gene caused by factors such as radiation and certain chemicals. In addition, errors made when DNA replicates just before cell division result in genetic changes.
When a suitable antibiotic is used to treat a population of bacteria, most of the bacteria will die, leaving room in the habitat for other organisms. A few of the bacteria may have a pre-existing gene or group of genes that gives them resistance to the antibiotic. The resistant individuals will survive and reproduce, spreading their genes through the growing population. Bacteria reproduce rapidly—some as often as every twenty minutes—so a resistant bacterial population can appear quickly.
The main driving driving factors behind antibiotic resistance are the overuse and misuse of antibiotics.— CDC (Centers for Disease Control and Prevention)
Use of Antibiotics
Antibiotics have been widely used around the world for both major and minor infections. They are sometimes prescribed in situations where they're not needed, such as in the treatment of viral infections. Antibiotics don't destroy viruses. The excessive use of antibiotics can increase the population of resistant bacteria.
It's a scary thought, but even mainstream health organizations are saying that there may soon be diseases that are untreatable, just as they were before the discovery of antibiotics. Some illnesses are taking longer to cure than in the past. Doctors could once choose from several different antibiotics to treat a disease; in some cases only one now works.
The Lytic Cycle of a Bacteriophage
Many phages have an interesting shape that reminds some people of a lunar lander. A phage is made of a protein coat surrounding a molecule of DNA or a similar chemical known as RNA (ribonucleic acid).
Phages infect bacteria in a process called the lytic cycle. The word "lytic" comes from the noun "lysis", which means splitting of a cell. The basic steps in the lytic cycle are as follows.
- A phage attaches to the membrane of a bacterial cell with its "tail".
- The phage then injects its DNA into the bacterial cell.
- The viral DNA takes over the cell's mechanisms for making DNA and protein so that new virus particles can be assembled.
- The new virus particles burst out of the cell.
- Each virus particle infects a new bacterial cell.
Some scientists consider viruses to be nonliving, since they aren't made of cells and they can't reproduce on their own. In addition, they can remain completely inactive for long periods of time. Nevertheless, their behavior as they attack and control a bacterium is amazing. Bacteriophages and other viruses seem to exist on the border between a collection of inanimate chemicals and life.
Although viruses have a relatively simple structure compared to cells and are sometimes considered to be nonliving, when they enter a cell they control it in exquisite detail. They are amazing entities that have major effects on our lives.
A Phage Attacks a Bacterial Cell
The History of Phage Therapy
The credit for the discovery of bacteriophages is given to two different men. In 1915, an English scientist named Frederick Twort published a paper about a bacteriolytic agent that he had discovered. In 1917, a self-taught Canadian scientist named Felix d'Herelle announced that he had discovered a microbe that killed bacteria. Both Twort and d'Herelle had discovered bacteriophages.
Felix d'Herelle started using phage therapy to treat humans in 1919. Other people soon did the same. The therapy had some success but was often ineffective. Scientists didn't know enough about phages to use them properly.
Phage therapy lost its importance in the west when antibiotics were discovered. However, Felix d'Herelle met some Soviet scientists who were interested in using phages to treat infections and helped them to establish the Eliava Institute in Georgia. This institute specializes in phage therapy research and still exists today. The therapy is popular in Georgia and seems to be very successful.
How Does the Therapy Work?
One advantage of phage therapy compared to antibiotic therapy is that the treatment is much more specific. A phage attaches to one particular strain of bacteria and leaves others untouched. Antibiotics may kill not only harmful bacteria but also helpful bacteria that live in our gut.
The specificity of phage therapy can also be a disadvantage, however. If the phage administered for an infection is the wrong type it will be ineffective. This is why Georgian scientists administer a mixture or "cocktail" of phages that have been known to help a specific type of infection in the past to increase the likelihood of a successful treatment.
The phage cocktail is administered in several ways. For example, to treat a stomach upset the cocktail is swallowed. To treat a mouth infection it's used as a mouthwash. To treat an infected skin wound it's placed on the wound. Infections can be tested to see what bacteria are present, but cocktails for common infections are kept in clinics.
Antibiotics are a big hammer. You want a guided missile.— Michael Schmidt, Medical University of South Carolina
Effectiveness and Safety
Information that is reaching the west from Georgia suggests that phage therapy is very helpful, but western scientists have to do their own research to submit to their health regulatory agencies. Scientists and health agencies want to see the results of clinical trials that follow rigorous scientific procedures before they accept claims that phages can treat disease and that they are safe to use.
Some scientists predict that phage therapy may work for a while, but eventually bacteria will become resistant to phages just as they have to antibiotics. Others say that this isn't likely, since unlike antibiotics viruses contain genes and will change their characteristics when their genetic composition changes. As in bacteria, viruses can pick up genes from other sources and genes can change due to mutations. Phages may develop genetic changes that enable them to overcome bacterial resistance, according to some scientists.
Even if phage therapy works for only a while, some researchers say that investigating the therapy is worth the effort. Phages may relieve discomfort and even save human lives while giving scientists the time they need to discover new treatments for bacterial infections.
What Are Bacterial Biofilms?
Phage Therapy in the Future
Scientists are not only testing phages to see if they fight infections but are also exploring ways to make phage therapy even more effective and safe. For example, in some cases enzymes produced by cells infected with phages seem to be helpful, which means that the enzymes could be used instead of the whole phage.
Some researchers are investigating ways to prevent the manufacture of an enzyme that breaks the bacterial cell open after new phages are made. Bacteria often contain harmful endotoxins, which could produce unpleasant symptoms when they're released. Scientists have discovered that a bacterial cell is killed while the phage DNA is inside the bacterium. Therefore it's not necessary for the bacterial cell to burst (from a human's point of view).
Experiments using phages in lab equipment suggests that some may be especially useful in the removal of bacterial biofilms. These films are made of a layer of bacteria attached to a surface and covered by a protective polysaccharide slime. Bacteria in biofilms are much harder to attack than free bacteria.
Once phages have killed bacteria, the immune system removes the phages and dead bacteria from the body. This process is so efficient that some phages are destroyed before they've done their job. Researchers are trying to solve this problem.
A Potentially Significant Announcement
In April 2017, a major announcement was made in the United States. Doctors at the University of California in San Diego reported that with the aid of many scientists they had successfully treated a patient with phage therapy. The patient had been near death due to an infection by a multidrug-resistant bacterium. There was apparently nothing else that the doctors could do to help him.
The doctors obtained phage strains from multiple organizations. In the lab, these strains had shown that they could fight the bacterium infecting the patient. The FDA (Food and Drug Administration) gave the doctors permission to administer the mixture of phages. The patient gradually recovered from the infection, though the recovery wasn't straight forward.
Two or three days after phage treatment was started (reports about the time vary), the patient woke from his coma. Later, however, the bacterium seemed have to have become resistant to the phages. Doctors overcame this hurdle by administering new phage strains as well as antibiotics. Eventually there was no evidence of the bacterium in the patient's body and he was able to go back to work.
At time of the patient's recovery, doctors emphasized that the therapy involved just one patient and they don't know the details about how the phages helped him. Since that time however, five additional patients have been cured of serious bacterial infections by the administration of a phage cocktail. The FDA allowed the treatments because the illnesses were emergencies and no approved treatments were available.
Effective Phage Treatment
In June 2018, the University of California, San Diego announced the creation of the Center for Phage Applications and Innovative Therapeutics. The center won't manufacture phage treatments but has connections to places that do. It will support treatments and clinical trials involving phage therapy.
Administering the Therapy
The need for a phage cocktail is a problem in western countries. At the moment, some regulatory agencies want safety tests to be done for each type of phage in the cocktail. In addition, cocktails for different diseases will need to be updated as bacteria and viruses change genetically or as new strains of bacteria are imported into a community. It would be expensive and time consuming to get each new strain of phage tested every time a cocktail changes. This is one problem that needs to be solved before phage therapy becomes widespread.
Doctors in North America can't yet prescribe phages as they do antibiotics. They may eventually be able to do do, however. Phage therapy seems to have great potential and could be a partial or complete answer to the problem of antibacterial resistance. The therapy has been used in some parts of the world for over ninety years. It's certainly worth investigating. It would be wonderful if it helps us defeat the troublesome and dangerous bacteria that attack us.
Antibiotic resistance facts from the Centers for Disease Control and Prevention (CDC)
Bacteriophage information from the University of South Carolina School of Medicine
Phage therapy is revitalized from the Nature journal
Phage therapy successfully used on a US patient from the University of California, San Diego.
U.S. center will fight infections with viruses from Science (American Association for the Advancement of Science)
Questions & Answers
© 2013 Linda Crampton