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, a phage invades a bacterial cell and uses it 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 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. However, 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 development 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 antibiotic now works.
The Lytic Cycle of a Bacteriophage
A phage has an interesting shape that reminds some people of a lunar lander. It's made of a protein coat surrounding a molecule of DNA or a similar chemical known as RNA (ribonucleic acid).
A phage infects 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.
- The phage attaches to the membrane of a bacterial cell with its "tail".
- The phage 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 are made.
- The new virus particles burst out of the cell.
- Each virus particle infects a new bacterial cell.
Many 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.
Viruses - Nonliving but Amazing
Although viruses have a relatively simple structure compared to cells and are often 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.
As early as 1919 d'Herelle was using phage therapy to treat humans. Other people soon did the same. Phage 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. Phage therapy is popular in Georgia and seems to be very successful.
How Does Phage 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
Antibiotic Resistance and Bacteriophage Therapy
The Effectiveness and Safety of Phage Therapy
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.
Clinical trials are being performed with phages. The results so far are promising, but more trials are needed before approval is sought for phage therapy for the general publIc. Scientists and health agencies want to see the results of experiments that follow rigorous scientific procedures before they accept claims that phages can treat disease.
As in bacteria, viruses can pick up genes from other sources and genes can change due to mutations. 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. Some phages will develop genetic changes that enable them to overcome bacterial resistance, according to these 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.
Removal of Phages from the Body
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.
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 newly formed phages from making an enzyme that bursts the bacterial cell open. 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 phages 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.
Phage Therapy in the West
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.
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.
© 2013 Linda Crampton
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