Jennifer Lake's Blog

August 4, 2009

Bacteriophage I

Filed under: DNA - RNA,Medicine — jenniferlake @ 7:56 am
Tags: , , , , ,
This is a complementary post to Understanding Virus and the Flu
Bacteriophage (laid the foundation for viral influenza research)
Q: What are phages and how do they “work”?

A: Bacteriophages (phages) are viruses that infect bacteria. Typical phages have hollow heads (where the phage DNA or RNA is stored) and tunnel tails, the tips of which have the ability to bind to specific molecules on the surface of their target bacteria. The viral DNA is then injected through the tail into the host cell, where it directs the production of progeny phages often over a hundred in half an hour. These “young” phages burst from the host cell (killing it) and infect more bacteria.[animal qualities are used to describe these phages, however in a previous post ‘Understanding Virus and the Flu’ I quoted a website that states phages are “possibly an enzyme”]

Q: Can therapeutic phages be developed against any infection?

A:Therapeutic phages can potentially be developed against any bacterial infection. Obviously, because of their “mode of action”, phages can not be used to treat viral infections (e.g. influenza or herpes).[phages can potentially be developed against any bacteria!]

Q: Can any phage be used for developing therapeutic phage preparation?

A: No. In general, there are two major types of phages, lytic and lysogenic. Only the lytic phages (also known as virulent phages) are a good choice for developing therapeutic phage preparations. Lytic phages multiply inside the cell, and release a burst of phages through the membrane, thus lysing the cell. Lysogenic phages, on the other hand, integrate their DNA into the host DNA creating a prophage. Prophage can escape from the original host (by cutting not only its DNA back, but possibly some genes of the host bacterium as well) and can integrate into a different one (the process is called transduction). Such phages are inappropriate candidates for phage therapy because of their “mode of action”, and because they can lead to transfer of virulence genes and those mediating resistance to antibiotics.

[the U Wisconsin website posted below the phage picture states: “Usually it is difficult to recognize lysogenic bacteria because lysogenic and nonlysogenic cells appear identical”. If that’s the situation today is it likely that the phage discovers, Twort (1915) and Felix d’Herelle (1917) would have discerned the difference in a lab? The U Wisc. page continues, “But in a few situations, the prophage supplies genetic information such that the lysogenic bacteria exhibit a new characteristic (new phenotype) not displayed by the nonlysogenic cell, a phenomena called ‘lysogenic conversion’. Lysogenic conversion has some interesting manifestations in pathogenic bacteria…” The interesting manifestations are that the lysogenic bacteria/phages can turn lethally virulent in an animal host. ] 

……(cont.)

Q: Why is there so much controversy about the efficacy of phages?

A:Phages were previously never given a fair and scientifically well-thought-through evaluation; quite often, the conclusions made about the phage therapy or even the nature of phages were unbelievably naive as assessed from what we know about phages today. Among specific reasons contributing to the early problems of phage therapy, as well as the questions on their efficacy, were:

Failure to select specific phages against the target bacteria in vitro, before using them in in-vivo models and/or in patients; [does this mean that in a ‘best case’ the phage therapy did nothing and in a ‘worst case’ it caused severe illness and death?] 

Lack of availability and/or reliability of bacterial laboratories for carefully identifying the pathogens involved, therefore making selection of specific phage impossible; [but they used phage-therapy anyway?]

Use of single phages in infections which involved mixtures of different bacteria; 

Failure to neutralize gastric acidity prior to oral phage administration;

Lack of knowledge that when treating bloodstream infections, endotoxins can be released as a result of lysis of bacteria which could lead to a further deterioration of the patient’s condition (which is a potential problem with antibiotics as well); [this was learned in the later 1940s, John F. Enders noted the ‘SOS’ response in bacteria, presumably from the effects of antibiotics, where dying bacteria release their viral components. Polio was a significant common result after antibiotic injection.]

Lack of understanding of the heterogeneity and “mode of action” of phage (e.g., differences between lytic and lysogenic phages in respect to their ability to act as therapeutic agents);

……(cont.)

Q: Have phages ever been licensed for human use?

A:Yes. Phage therapy products were licensed for sale in the United States in 1930s. The Ministry of Health of the former Soviet Union routinely licensed active phage preparations for the use in humans. ; It is likely that therapeutic phages used (and sold) in Eastern Europe were also licensed by appropriate public health authority (e.g., ministry of health).

Q: Have phages ever been produced for commercial use?

A:Yes. In the 1930s, a large US pharmaceutical company listed phages among its biological therapies and offered them for sale. Phages were used at the Institute Pasteur in Paris, France, and were sold in Eastern Europe, and all over the territory of the former Soviet Union.

Q: Can the bacteria develop resistance against phages?

A: Bacteria can develop resistance against both antibiotics and phages. However, there are some very important differences to favor phages in this context:

Development of a new antibiotic is a very expensive and time consuming process; it can take over 10 years and several million dollars to develop, and to bring to the market, a new antibiotic. Developing of a new phage, on the other hand, can potentially be accomplished in days, at a much lower expense.

 

Science may approach a point when no effective antibiotics can be chemically developed (at least for a while) to treat certain multi-drug resistant micro-organisms. Since selection of active phages is a natural process, evolutionary arguments support the idea that active phage can be selected against every resistant bacterium, by an ever ongoing process of natural selection. [multi-drug resistant organisms, presumably ‘not natural’, would indeed theoretically ‘select’ for evolving phages in order to eventually ‘balance’ in some kind of eco-harmony but are they really suggesting that drug manufacturers are going to wait-it-out for ‘nature’ to correct this problem of mutant bacteria? Agressive species (such as the new ‘superbugs’) often cause the extinction of lesser competitive lifeforms, that’s nature’s way too.]

Photo above of bacteriophage ‘T4’

from http://bioinfo.bact.wisc.edu/themicrobialworld/Phage.html

This website notes that Twort and d’Herelle made their ‘phage’ observations by dissolving intestinal bacteria “by addition of a bacteria-free filtrate obtained from sewage”, adding that “Most research has been done on the phages that attack E. coli, especially the T-phages and the phage lambda”. The T-phages (T1 through T7) are a group of seven lytic phages known to infect E. coli. The lambda is a lysogenic phage (transfers DNA).

Bacteriophage, part II https://jenniferlake.wordpress.com/2009/08/04/bacteriophage-ii/

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