Sunday, November 25, 2007

When Phages Attack: The War Against the Bacteria


Back in my high school days and my serious interests in micro-organisms, I pondered to myself, why don’t scientists modify bacteriophages to specifically target pathogenic bacteria. As it is, scientists today have increasingly researched this possibility as an alternative to conventional drug therapies. The use of bacteriophages to treat bacterial infection is called bacteriophage (or phage) therapy.

Bacteriophages have a high affinity towards specific receptor proteins bound on the surfaces of bacteria. This specificity allows the theoretical use of these viruses as treatment alternatives against pathogenic bacteria against human, animals, and even plants. The mechanism behind phage therapy is that the bacteria will lysis upon invasion of the bacteriophage, thus curing the disease. Because bacteriophages have a high specificity towards a specific type of bacteria, they would make excellent use since the phages would not damage other cells, unlike conventional drug therapies.

One of the issues dealing with conventional drug therapies is the penetration of biofilms. Drugs have a difficulty in being effective in the presence of a biofilm. Phage therapy doesn’t have this issue since the phages could bypass the biofilm and destroy the bacteria.

In drug therapies, bacteria can evolve to develop resistances against drugs, as in the case with MRSA. With phage therapy, the evolution of resistance to the phages theoretically should be balanced out with the evolution of the phage to continued infection of the bacteria. One study showed promising results in the use of phage therapy.

In Britain, H. W. Smith and M. B. Huggins (1982, 1983) carried out a series of studies on use of phages in systemic E. coli infections in mice and then in diarrheal disease in young calves. For example, they found that injecting 106 colony-forming units of a particular pathogenic strain intramuscularly killed 10/10 of the mice, but none died if they simultaneously injected 104 plaque-forming units of a phage selected against the K1 capsule antigen of that bacterial strain. This phage treatment was more effective than using such antibiotics as tetracycline, streptomycin, ampicillin or trimethoprim/sulfafurazole. Furthermore, the resistant bacteria that emerged had lost their capsule and were far less virulent.

Another possibility for phage therapy is to be used in conjunction with conventional drug therapies. Since some bacteriophages are lysogenic, these phages are able to combine their genetic material with the bacterial cell’s DNA. This insertion of genetic material may be able to code for proteins and enzymes that could weaken the bacteria’s defenses. After the weakening of the defense mechanism, conventional drug therapies would then destroy the bacteria as they normally would.

With the new research into phage therapy and the efforts put into modifications of genes, I leave you with this question. Would it not be possible to manufacture specific bacteriophages to target any bacteria in the near future?


Sources:

http://en.wikipedia.org/wiki/Phage_therapy

http://www.biotechjournal.com/Journal/feb2003/Article1text.htm

http://academic.evergreen.edu/projects/phage/phagetherapy/phagetherapy.htm

2 comments:

Spokesthingy said...

Below are some references that will show you that phage therapy is being used to cure bacterial infections every day - hubris prevents Western doctors from employing the technique:

Choosing to let patients with superbug infections die rather than phage them!!!!

It is my humble opinion that the antibiotic-resistance superbug crisis is the mother of all regulatory-scientific-environmental misadventures; however, the absurdity of the superbug crisis consists of the fact that it can be demonstrated that we had technology, namely bacteriophage therapy, long before we created the antibiotic-resistance superbug crisis through massive abuse of antibiotics and other antimicrobials. Additionally many politicians, bureaucrats, scientists and members of the public health community are or should be well informed about phage therapy which can cure many superbug infections. In spite of a voluminous literature attesting to the scientific validity, safety and medical effectiveness of phage therapy (see http://www.phage.org and find phage therapy references), there are still phage therapy deniers who would resist the careful deployment of these weapons of mass-destruction for specific pathogens in the war with superbugs (It would appear that public health systems are AWOL from the war with superbugs).

What is Phage Therapy? Prior to the discovery and widespread use of antibiotics, bacterial infections were treated worldwide by the administration of bacteriophages. Bacteriophages or phages are highly specific viruses that invade bacterial cells and, in the case of lytic phages, disrupt bacterial metabolism and cause the bacterium to die. Interestingly it was the French-Canadian microbiologist, Felix d'Herelle, while working at the Institute Pasteur in Paris in 1917 who is credited with discovering and promoting phage therapy. While the use of phage therapy was discontinued in the West soon after the discovery of antibiotics they continued to be utilized in Eastern Europe and today many infections untreatable with antibiotics can be treated in clinics in Georgia (Europe) and Poland. Once one accepts the fact that it requires microscopes to see the world of bacteria and bacteriophages, phage therapy may be compared to any biological control methodology and can conceptually be described as: What a cat is to a mouse the right bacteriophage is to a specific bacterium or superbug. Phage therapy has been going on in nature as a balancing force in the evolution of microbes for a long time. Medical phage therapy is simply the intervention by humans to ensure that the balance is in favour of bacteriophages over susceptible bacterial pathogens! While there is considerable expertise on phage therapy in Canada at the research level, as can be substantiated by googling phage therapy ("pages from Canada" only), medical phage therapy is not currently approved or practised in Canada; however, according to a letter signed by the former federal health minister phage therapy can be made available legally to Canadian patients under the Special Access Program of our Food & Drugs Act! Additionally, there are moral and ethical reasons for making phage therapy available since Canada appears to be a member of The World Medical Association which states: "In the treatment of a patient, where proven prophylactic, diagnostic and

therapeutic methods do not exist or have been ineffective, the physician, with informed consent from the patient, must be free to use unproven or new prophylactic, diagnostic and therapeutic measures, if in the physician's judgement it offers hope of saving life." ( see below for quote source ).

A discussion of phage therapy is currently very timely, not only because too many patients are dying of superbug infections; but also because of the recent release of the Canadian film: Killer Cure: The Amazing Adventures of Bacteriophage and the June 2006 release of the book by Thomas Haeusler entitled, Viruses vs. Superbugs, a solution to the antibiotics crisis? ( see http://www.bacteriophagetherapy.info ) - both are available at Ottawa libraries. Additionally, the record of an excellent questions-and-answers session with Dr. Roger Johnson of the Public Health Agency of Canada can be found at http://meristem.com/topstories/ts06_08.html .

Further, the phage therapy file has dramatically changed during the last few months because the US Food and Drug Administration (FDA) has amended the US food additive regulations to provide for the safe use of a bacteriophage preparation on ready-to-eat meat and poultry products as an antimicrobial agent against Listeria monocytogenes (see http://www.fda.gov/OHRMS/DOCKETS/98fr/02f-0316-nfr0001.pdf ). This excellent submission evaluation changes the scientific validity of phage therapy from Eastern European science, which, sadly, too many of us Westerners dismiss with hubris and bias as not credible, to approved and supported by the all-knowing and all-seeing FDA at least for ready-to-eat meats. An enlightening FDA questions-and-answers document can be found at http://www.cfsan.fda.gov/~dms/opabacqa.html .

Superbugs are everybody’s business because superbugs make everybody their business and every North American should study the above references because sooner or later everybody will be faced with an infection or know a relative or friend who will be suffering or dying with one. Withholding such treatment from patients when antibiotics are failing ought to be a crime; however, those who have the money, knowledge and time to travel when faced with an infection where antibiotics are failing may be able to get phage therapy treatment in Georgia ( http://www.phagetherapycenter.com ) or Poland - http://www.aite.wroclaw.pl/phages/phages.html . A record of a trip to Georgia to get phage therapy treatment by UK citizens can be seen at http://www.relax-well.co.uk/news.html .

What is even more surprising and frustrating is that an American company, Phage International Inc., ( http://www.phageinternational.com ) would probably be willing and able to set up a phage therapy clinic in any country if the right regulatory climate existed. A recent article describing how foreigners from many countries are treated at their Phage Therapy Center in Tbilisi, Georgia can be found at http://www.phagetherapycenter.com/doc/sjbizjournal.pdf .

Since January 1, 2000 as many 87,000 Canadians may have died of superbug bacterial infections and there is not even a memorial for them, although some people are starting to wear blue ribbons in memory of superbug victims. Would it not be nice if the Canadian governments, public health officials and media got together and funded the Felix d'Herelle Center for Phage Therapy to provide the phage therapy treatment option for patients when antibiotics fail and we have nothing left to offer them?

P.S.: WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI PARAGRAPH 32:

"In the treatment of a patient, where proven prophylactic, diagnostic and
therapeutic methods do not exist or have been ineffective, the physician,
with informed consent from the patient, must be free to use unproven or new
prophylactic, diagnostic and therapeutic measures, if in the physician's
judgement it offers hope of saving life, re-establishing health or
alleviating suffering. Where possible, these measures should be made the
object of research, designed to evaluate their safety and efficacy. In all
cases, new information should be recorded and, where appropriate, published.
The other relevant guidelines of this Declaration should be followed."

FROM: The World Medical Association:

http://www.wma.net/e/policy/b3.htm - and

http://www.aite.wroclaw.pl/phages/phages.html

Dominic B. said...

I has been proven that some bacteria can send "suicide messages" to other bacteria. These message urge the cells to kill themselves probably when a phage is attacking them. Here is a website:

http://www.tfot.info/news/1039/
bacteria-suicide-mechanism
-might-lead-to-new-drugs.html