biology

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Bacteriophage as an antibiotic

WHAT PROPERTIES NEEDED AS AN ANTIBIOTIC?

The antibiotic must be effective in the treatment of infection because of their selective toxicity. That means the drug should kill or effect against the invading desired organism without harming the cells of the host. In most of the cases, this toxicity is just relative rather than absolute, requiring that the concentration of the drug be carefully controlled to attack the microorganism while still being tolerated by the host.

WHY PHAGES AS ANTIBIOTIC?

As the PHAGE viruses can infect and kill the bacteria, they can be used as a drug targets against the Bacteria. Phage Therapy: Phage therapy is the use of lytic phages to kill specific acteria as an alternative to antibiotic.

BACTERIOPHAGES UDERGOING LYSIS OF THE BACTERIA

The lytic mechanism of the Bacteriophages ensures the effective antibiotic mechanism of the Phages. The other useful thing is that the specific type of Bacteriophage attacks only the corresponding bacteria and so the other normal bacteria will not be affected by the specific Phage Therapy targeted to the aimed bacteria. So, the Phages have more specificity than all antibiotics in attacking the bacteria.

Host Vs Phages

The phages are immunogenic and could initiate the immune responses. This effect may limit the uses of Phages because the Bacteriophages may be destroyed by our immune system even before attacking the desired target bacteria and also the strong immune responses may trigger the allergic reactions and also the human immune system produces antibodies against the Phages.

Despite these matters, the good news is that their clinical uses reveal only very few side effects or allergic reaction. The best way to avoid the sensitization is to use the Phages only when it is necessary as in the case of multidrug resistant infection and using the Intra Venous IV Administration method.

BACTERIOPHAGE AGAINST TB

Tuberculosis, one of the oldest diseases known to affect humans, is caused by bacteria belonging to the Mycobacterium tuberculosis complex. The disease usually affects the lungs, although in up to one-third of cases other organs are involved. If properly treated, tuberculosis caused by drug-susceptible strains is curable in virtually all cases. If untreated, the disease may be fatal within 5 years in more than half of cases. Transmission usually takes place through the airborne spread of droplet nuclei produces by patients with infectious pulmonary tuberculosis.

MULTIDRUG RESISTANT TUBERCULOSIS: This condition arises when the Bacteria undergo point mutation in their genome which occurs at low but predictable rates. There are two types of drug resistant

  1. Primary drug resistant: This occurs when the strain infects the one who has never been treated before and
  2. Acquired drug resistant: In which, the resistant develops during treatment with inappropriate regimen.

Apart from the resistant, some of the patients are not appropriate to give the usual dose of conventional treatment due to their co existing diseases like renal failure, hepatitis or liver failure.

MYCOBACTERIOPHAGE

Mycobacteriophages are the bacteriophages that infect against mycobacteria, the bacteria causing Tuberculosis and many other diseases like Leprosy. Mycobacteriophages were first discovered by the in 1946.They are the double stranded DNA viruses with non contractile tail belonging to the Siphoviridae family of the Bacteriophage. They also infect the pathogenic bacilli of the Mycobacterium Tuberculosis complex and now more than 250 mycobacteriophages have been indentified. They are either lytic or temperate. Some mycobacteriophages like DS6A can exclusively infect the Mycobacterium tuberculosis alone. Phages like 13, D 29, TM4, Bxz2 and Chel 2 infect both Mycobacterium tuberculosis and other Mycobacterium bacteria. Their morphological variation is limited but their genomes show extra ordinary genetic variability. The implications of phages in mycobacterial diseases may be greater than previously realized.

PHAGE THERAPY

We can use lytic phages to kill specifically pathogenic bacteria as an alternative to antibiotics treatment especially for the multidrug resistant Tuberculosis. Lack of knowledge of bacteriophage biology and the quality monitoring during the preparation of therapeutic stocks had made the therapy difficult though the first known therapeutic use was in 1919.The M. Tuberculosis infections are hard to treat because the bacteria are naturally resistant to many antibiotic. The bacilli may remain in the latent or dormant state avoiding the action of drugs that require replication of the bacteria. So, the treatment of Tuberculosis requires multiple drugs for extended periods of time to effectively cure and avoid the drug resistant. The minimal duration for the treatment is four months with four drugs and then two months with two drugs. The most important thing is the emergence of multi drugs resistant strains and that makes the Phage Therapy more interested.

Dr Margaret Chan, the director-general of the World Health Organization said,“The situation is already alarming, and poised to grow much worse very quickly”. She and Bill Gates also stated that they only had little help from the modern drugs for the disease that is affecting 9 millions people each year killing nearly 2 millions of them. The conventional drugs are useless against some strains of tuberculosis and they addressed the situation OUT OF CONTROL and A POTENTIALLY EXPLOSIVE

TIM JOHNSON, Mc Clatchy Newspapers

Animal study: One of the Mycobacteriophage, DS6A, showed reduction in the observed in the lesions in spleen, lungs and livers of guinea pigs infected with (Challenged with) Mycobacterium tuberculosis and the study showed that the anti bacterial effect of the phages is at least as good as Isoniazid monotherapy. The results are promising in the treatment of tuberculosis using phages.

MYCOBACTERIM INSIDE THE MACROPHAGES: Mycobacterium can reside in the macrophage cells of our immune system. They can even persist inside the phagolysosome where many bacteria and pathogens are killed. It was uncertain whether the mycobacteriophages can survive and replicate inside the hostile intra-cellular environment with reduced PH.

MYCOBACTERIUM SMEGMATIS, THE VEHICLE INTO THE MACROPHAGES: The above problem can be solved by using the vector bacterium Mycobacterium smegmatis. The technology was introduced in 2002. In this technology, the non-virulent bacteria Mycobacterium smegmatis act like a carrier into the macrophages.

Dr Margaret Chan, the director-general of the World Health Organization said,“The situation is already alarming, and poised to grow much worse very quickly”. She and Bill Gates also stated that they only had little help from the modern drugs for the disease that is affecting 9 millions people each year killing nearly 2 millions of them. The conventional drugs are useless against some strains of tuberculosis and they addressed the situation OUT OF CONTROL and A POTENTIALLY EXPLOSIVE

TIM JOHNSON, Mc Clatchy Newspapers

Animal study: One of the Mycobacteriophage, DS6A, showed reduction in the observed in the lesions in spleen, lungs and livers of guinea pigs infected with (Challenged with) Mycobacterium tuberculosis and the study showed that the anti bacterial effect of the phages is at least as good as Isoniazid monotherapy. The results are promising in the treatment of tuberculosis using phages.

MYCOBACTERIM INSIDE THE MACROPHAGES: Mycobacterium can reside in the macrophage cells of our immune system. They can even persist inside the phagolysosome where many bacteria and pathogens are killed. It was uncertain whether the mycobacteriophages can survive and replicate inside the hostile intra-cellular environment with reduced PH.

MYCOBACTERIUM SMEGMATIS, THE VEHICLE INTO THE MACROPHAGES: The above problem can be solved by using the vector bacterium Mycobacterium smegmatis. The technology was introduced in 2002. In this technology, the non-virulent bacteria Mycobacterium smegmatis act like a carrier into the macrophages.

MYCOBACTERIUM SMEGMATIS

Macrophages infected with the Mycobacterium Tuberculosis or Mycobacterium avium were treated with the additional Mycobacterium smegmatis infected with Mycobacteriophage TM4. After they are ingested and destructed by the macrophages, the TM4 phages were released within the macrophages infecting and destroying the pathogenic bacteria even within the macrophages. The experiments showed the significant reduction of both the Mycobacterium tuberculosis and Mycobacterium avium.

D29bacteriophages: This D29 are capable of entering the Macrophages without the need of any carrier and they can infect the mycobacterium and kill them effectively.

So, the mechanisms of action of mycobacteriophages are completely different from the conventional drugs and will be so important in the multi-drug resistant cases. The Phage therapy also dose not need repeat dosing because the viruses do increase within the target bacteria and new virions are released on lysis. The endotoxin may be released into the body after the bacteria has been lysed and this could trigger the immune reactions but till now the clinical use of bacteriophages revealed only very few cases of side effects or allergic reaction indicating that our human body can really tolerate them. The other advantage is that they are cheaper and easier to produce than antibiotics.

REFERENCES

  1. LIPPINCOTT's ILLUSTRATED REVIEWS of MICROBIOLOGY 2007 EDITION
  2. HORACE T. ADAMS CONTEMPORARY TRENDS IN BACTERIOPHAGE RESEARCH 2009 EDITION
  3. RICHARD CALENDAR THE OXFORD TEXT BOOK OF “THE BACTERIOPHAGE” 2nd EDITION 2006
  4. http://www.microphage.com/technology/phageBiology.cfm
  5. WHO, world health organization, Global Tuberculosis control Geneva
  6. Harrison text book of Practice of Medicine, USA 6th edition
  7. Fuller, KJ and Hatfull GF 1997 Mycobacteriophage L5 infection of Mycobacterium bovis BCG implications for phage genetic in the slow-growing mycobacteria Mol Microbiaol 26 755-766
  8. Kaufmann SH 2002 Protection against Tuberculosis cytokines T cells and macrophages Ann Rheum Dis 61 Sulll 2 ii54-58
  9. BroxmeyerL Sonsowaka DMiltner 2002 killing of Mycobacterium by a mycobacteriophage delivered by non virulent mycobacterium, model for phage therapy of intracellular bacterial pathogen, J infect Dis 1155-1160
  10. Trollip A Albert H and Maskell 2001 Bacteriophage based technology for the rapid diagnosis and drug susceptibility testing of tuberculosis Am Clin Lab 20: 39-42