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Bacteriophages are viruses that can infect and destroy bacteria. This property of the bacteriophages was exploited and used against bacteria that were anti-biotic resistant. The major constraint with antibiotics was that bacteria developed resistance against these antibiotics, enabling them to survive despite the application of the specific antibiotic drugs (Berkowitz 1995). This proved to be a severe problem in destroying the bacteria and preventing the carnage brought about by them. This proved the platform for the advent of bacteriophage therapeutics. The use of bacteriophages as therapeutic agents was made possible, since they had more specificity than the usual drugs and the phages were successful in penetrating the biofilm covered by the polysaccharide layer (Aguita 2009), which was found to be an obstacle for the common drugs in reaching the bacteria and killing them. Bacteriophage therapy finds its marks in a wide range of medical fields such as Human medicine, Veterinary Science, Dentistry and even Agriculture.
Bacteriophages are any viruses that can attack and kill bacteria. Bacteriophages have an outer protein capsid that holds the genetic material inside (Mc Grath et al 2007). The body can be divided into a head, collar and tail region. The head holds the genetic material and the tail has fibers that enable the holding of the bacteriophages onto the bacterial walls and eventually resulting in passing of the genetic material into the bacteria to enable the replication of phages and destruction of the bacteria. The bacteriophage lifecycle can be of two ways.
The lytic cycle results in the death of the bacterial host (JG Black 2002). The cycle is of five stages, (seen in Fig 1.)
Attachment - the bacteriophage attaches to the surface of the bacteria by the help of its tail fibers.
Penetration - the phage releases enzymes to weaken the cell wall of the bacteria and then injects its genetic material into the bacteria.
Biosynthesis - the phage DNA is integrated with the host DNA and this makes the host to synthesize the phage DNA and other related components.
Assembly - the phage DNA and components that were synthesized are put together to form new phage particles.
Maturation & Lysis - after the assembly is complete, the phage particles produce and enzyme that breaks the bacterial cell wall and causing the lysis of the bacteria and releasing the phages from inside.
This cycle is complementary to the lytic cycle of the bacteriophage (Bertani 1953). The following are the steps of lysogenic cycles, (seen in Fig 1.)
Entry - the genetic material of the bacteriophage enters the host bacterial cell
Integration - the viral DNA integrates with the host DNA
Replication - the host cell DNA copies the viral chromosomes
Cell division - the host cell divides and along with the host genetic material, the viral genetic material is transmitted into the daughter bacterial cells.
Lytic cycle - after the cell division, the dormant viral DNA enters lytic cycle and it follows similar steps from the lytic cycle resulting in the multiplication of the phage particles and their release.
The lysogenic cycle of bacteriophages, the lysogeny doesn't result in the lysis of the host cells and hence the phages that exhibit lysogeny are not ideal in developing the phage therapy.
Fig. 1 - Shows the complementarity between the lytic and lysogenic cycles of Bacteriophage multiplication (source: Modified from Lytic & Lysogenic cycle, Wikipedia)
Mechanism of attack on Host cells
The expected end result in phage therapy is the lysis of the bacterial host cells infected by the phages. There are many different strategies employed by the phages to lyse the infected bacteria. The phages with double stranded DNA; the lysis of the bacterial hosts is catalyzed by the proteins Holin and Endolysin (Loessner et al 1998). Holin works as a transporter, it helps the movement of the endolysin enzyme to the bacterial peptidoglycan layer. Endolysin with the help of its catalytic properties enables the degradation of the peptidoglycan layer. Unlike the double stranded DNA possessing phages, the smaller DNA or RNA phages have proteins that interfere with the peptidoglycan producing enzymes in the host cells and this eventually helps the phages to cause lysis of the host cells.
Bacterial Host Specificity
The common antibiotics that are used have a wide range of host specificity, this makes them lose the meaning for "specificity" and hence they do not tend to be very efficient with their targets. However, the host range of phages is much narrower in comparison (Nunes et al 1978). Moreover, the phages are found to be less harmful to the body flora unlike the commonly used antibiotics. There are a large variety of host specific phage strains that have been developed to target the specific pathogens.
Advantage of Phage Therapy over Antibiotics (Table 1)
Table 1. Shows the advantages of Phages over Antibiotics
(Source: Modified from Phagetherapycenter.com)
Wide spectrum range
Phages specifically lyse the target bacteria, unlike Antibiotics which also target the useful microbial flora inside the body
Replication at the site of infection
They are processed by the metabolic functions inside the body.
Phage replication at the site makes them available at the site of infection and thereby makes them more effective
Minimal side effects observed
Multiple side effects
The sides effects in Phages are mainly due to the endotoxins from the lysed bacteria, and not from the Phage particle as such
Phage resistant bacteria remain susceptible to other phages having same range
Anti-biotic resistance is not just limited to the target bacteria.
Wide spectrum of antibiotics creates many mutant strains of bacteria that are antibiotic resistant and not just the target bacteria that change
Easier to select phages that can target antibiotic resistant bacteria. Usually takes just days or weeks
Developing newer drugs to target the antibiotic resistant bacteria is time consuming.
Easier to identify strains of phages and attack the antibiotic resistant bacteria.
Infections targeted by Bacteriophage Therapy
In 1917, when the bacteriophage was discovered by Felix d'Herelle at the Pasteur Institute in Paris, there were many hoping to use bacteriophages as therapeutic agents and in 1920s, Eliava Institute, Georgia started research in this and tried to put the same into practice. At the time, phage therapy was targeted towards dysentery, typhoid, sepsis and cholera (Carlton 1999). But the rapid discovery of several antibiotics put the phage therapy to rest. Although it was later identified that the phage therapy could prove far more effective compared to the antibiotics; research showed that bacteriophages could be used as both curative and preventive agents. In the treatment of dysentery, bacteriophages not only manage to destroy the microbes but also prevent the infection from spreading further, provided the medication was given at the initial stages of the intestinal infection. Present research has paved way for phage therapy to be used in a wide variety of diseases and infections such as tuberculosis, cholera, typhoid etc. A new form of medication evolved which used the antibiotics along with the phage therapy resulting in improved cases of recovery. According to Saratov's Scientific Research Center, Georgia, phage therapy has been implemented and successful clinical studies were performed against infectious-allergic rinosinusopathy, infectious-allergic bronchial asthma, post-surgical non-epidemic infections, urinary tract infection, epidermal infections in babies etc (Saratov's Scientific Research Centre webpage).
Disadvantages of Bacteriophage Therapy (Matsuzaki et al. 2005)
Lysogeny and Harmful genes: the phage genetic material that integrates with the host cell genetic material can help transmitting antibiotic resistant between genes of the host. Hence phages following lysogenic cycle are not useful in phage therapy.
Bacterial Growth Impact: the growth environment of bacteria can alter its genetic material to adapt to the changes and this can affect their susceptibility to the phages.
Bacterial Endotoxins: when the bacteria are lysed, they release endotoxins can be harmful to the body.
Pharmacokinetic data: the lack sufficient pharmacokinetic data, predictions for the clinical efficacy of phages on target bacteria is missing.
Host range: the narrow specificity of phages prevents them from infecting bacteria belonging to the same subgroup within the species. Hence identification of the correct species of infection causing bacteria is vital in phage therapy.
Contamination: Any bacterial contamination present in the phage products could prove fatal to the patients.
The discovery of antibiotic resistant bacteria is rising alarmingly and the discovery of specific antibiotics targeting these takes up lot of time and resources. Bacteriophages on the other hand have high specificity towards their target bacterial hosts. This property when properly exploited can prove useful and make significant contribution in fighting infections caused by antibiotic resistant bacteria. The phage therapy can be used both as curative and preventive therapy. This not only increases the scope of phage therapy but also provides new platforms to challenge a number of infections.