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What are
phages and how do they kill bacteria?
Bacteriophages (phages) are viruses that infect bacteria.
They are the most abundant microorganisms on earth. 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 phage DNA is then injected through the phage tail
into the host cell, where it directs the production of progeny
phages, often more than 100 in 20 - 40 minutes. These "young"
phages burst from the host cell, killing it, and infect more
bacteria. See a simulation of the above-described
process in the right margin (Requires RealPlayer).
Phages are very specific. They can only infect their targeted
bacteria, and they have no effect on any human, animal,
plant, insect, etc. cells.
How
common are bacteriophages in nature?
Bacteriophages are the most common and ubiquitous organisms
on Earth. Their total number is estimated to be approximately
1032. This value is equal to
100,000,000,000,000,000,000,000,000,000,000 phage particles.
Some additional facts/examples:
- More than 100 million phage species exist
- 1 milliliter of non-polluted water may contain 100,000,000
phages (one milliliter equals one cubic centimeter, or about
two drops from an eyedropper).
- Poultry products, fruits and vegetables, and cheese sold
at retail often contain more than 100,000,000 phages per gram
of food.
- Phages have been found in commercial sera.
- Phages have been found in human vaccines.
- Phages are common in the human mouth, where they are
harbored in dental plaque and saliva.
- Phages are found, in prodigious numbers, in the
gastrointestinal tracts of humans and other animals.
Have
bacteriophages been found in or on foods?
Yes, bacteriophages have been isolated from drinking water
and from a wide range of food products, including ground beef,
pork sausage, chicken, farmed freshwater fish, common carp and
marine fish, oil sardines, raw skim milk, and cheese. In one
published study, bacteriophages were recovered from 100% of
examined fresh chicken and pork sausage samples and from 33% of
delicatessen meat samples. In another study, phages were found
in 48 to 100% of the samples of fresh chicken breasts, fresh
ground beef, fresh pork sausage, canned corned beef, and frozen
mixed vegetables. Several other studies have suggested that 100%
of the ground beef and chicken meat sold at retail contain
various levels of various bacteriophages. Phages also have been
found in animal feed. Humans consume phages daily by drinking
water and by eating unprocessed foods.
Do
organically grown foods contain phages?
Yes. Organically grown foods are likely to contain more
phages than do non-organic foods treated with various chemicals,
because many chemicals used to improve the safety of foods, or
to preserve and increase the shelf-life of foods, kill phages as
well as potentially pathogenic bacteria and potentially
beneficial probiotic bacteria.
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Can therapeutic phages be developed against any infection?
Therapeutic phages potentially can be developed against any
bacterial infection. However, because of their mode of action,
phages are not effective against viral infections (e.g.,
influenza).
Can any phage be used to develop phage preparations for food
safety applications and for therapeutic use in humans or other
animals?
In general, there are two major types of phages: “virulent”
(also called “lytic”) and “temperate” (sometimes mistakenly
called “lysogenic”). Only lytic phages are suitable for
therapeutic phage preparations. At the end of their life cycles
inside their specific bacterial host cells, lytic phages release
a burst of progeny phages through the cytoplasmic/outer
membrane, thus lysing the bacteria. On the other hand, some
temperate phages (which, by definition, do not lyse all of their
bacterial host cells) are lysogenic; i.e., they integrate their
DNA into their initial host cell’s DNA and create a “prophage,”
which subsequently may transfer, via the process of
transduction, some of the original host bacterium’s DNA to other
host cells. Such phages are inappropriate candidates for phage
therapy because they do not lyse all of their host cells, and
because they may transfer genes encoding bacterial virulence
factors and resistance to various antibiotics. All phage
preparations developed by Intralytix contain only lytic phages.
How safe are phage preparations developed for therapeutic
applications?
Phages are very safe. They are the most common and ubiquitous
organisms on this planet and humans consume them daily by
drinking water, eating fresh foods, etc. Furthermore, phages
have been used, since 1919, to treat various bacterial
infections of humans and other animals. Large amounts of phages
have been administered, without serious side effects, to humans:
- orally, in tablet or liquid formulations
- rectally
- locally (skin, eye, ear, nasal mucosa, etc.), in tampons,
rinses and creams
- as aerosols or intrapleural injections
- intravenously
A few minor side effects have been
reported in patients undergoing phage therapy, and those that
were seen seemed to be directly associated with the therapeutic
process. For example, mild pain in the liver area (lasting
several hours) was reported in one study conducted in Poland.
The authors suggested that the response was related to extensive
liberation of bacterial endotoxins from the phage-lysed
bacteria. It should be mentioned that this side effect also may
occur during antibiotic therapy.
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Have phage preparations ever been produced commercially?
Yes. During the 1930s-1940s, Eli Lily and Co. manufactured
several therapeutic phage products for treating various
bacterial infections, including skin infections. Other major
companies involved in therapeutic phage production in the USA
included E.R. Squibb and Sons and Swan-Myers (now Abbot
Laboratories). In Europe, phage preparations were produced by,
and used for therapy at, the Pasteur Institute (Paris, France),
and the Russian and German Armies routinely used therapeutic
phage preparations during World War II. In fact, phage therapy
has been utilized, from the 1920s to the current day, in Eastern
Europe and the former Soviet Union. At the present time,
therapeutic phage preparations are being manufactured and sold
in some Eastern European countries; e.g., the Republic of
Georgia, Russia, and Poland.
How do
phages compare to antibiotics?
| |
Phages |
Antibiotics |
| Efficiency |
Phages are highly effective
in killing their targeted bacteria (i.e., their action
is bactericidal) |
Some antibiotics (e.g., chloramphenicol) are bacteriostatic;
i.e., they inhibit the growth of bacteria rather then killing
them, which may help promote emergence of resistance against
those antibiotics.
|
| Specificity |
Phages are very specific, and they affect the targeted
bacterium only; therefore, "dysbiosis" (and chances of
developing secondary infections) is avoided. |
Antibiotics are much less specific and they target not only the
pathogenic microorganisms but also a normal microflora. This can
affect the microbial balance in the gut, which, in turn, often
leads to serious secondary infections.
|
| Side Effects |
Humans are exposed to phages throughout life, and well
tolerate them. No serious side effects have been described for
therapeutic phages.
|
Multiple side effects, including yeast infections, intestinal
disorders, and allergies are often associated with antibiotic
therapy. |
| Bacterial Resistance |
Because of phages' specificity, their use is not likely to
select for phage resistance in other (i.e., not-targeted)
bacterial species. |
Because of their broad spectrum of activity, antibiotics may
select for resistant mutants of many pathogenic bacterial
species, not just for resistant mutants of the targeted
bacteria.
|
Time
Before Use |
Because of the high specificity of phages, the
disease-causing bacterium has to be identified before the phage
therapy can be successfully employed. |
Antibiotic therapy can be initiated without precise
identification of the disease-causing bacterium. |
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Can
bacteria develop resistance against phages?
Antibiotic- and phage-resistant mutants of pathogenic
bacteria can arise; however, if that occurs, there are at least
two important factors that favor the development of new,
therapeutically effective phage preparations. First, since
phages have been co-evolving with bacteria for approximately 3.5
billion years, new lytic phages active against emerging
phage-resistant mutants are constantly arising in the
environment. Therefore, it should be possible to harness the
power of this co-evolutionary process to ensure the continuous
and ready availability/isolation of phages effective against
mutant bacterial pathogens. Second, because the mechanisms by
which antibiotics and phages kill bacteria are very different,
phage therapy will not enhance the emergence of
antibiotic-resistant bacteria, which is a major concern with
antibiotic therapy and with widespread use of antibiotics in
agriculture. Thus, phages provide a much-needed additional
modality for dealing with bacterial infections, including
infections caused by bacteria that are completely resistant to,
and therefore untreatable with all currently available
antibiotics.
Which phage preparation of Intralytix, Inc. did the FDA approve?
The United States Food and Drug Administration (FDA)
approved a phage preparation (designated “ListShield™”) developed
by Intralytix, Inc. ListShield™ is 100% natural, and safe and
effective product for reducing contamination of various
ready-to-eat foods with Listeria monocytogenes; thereby,
increasing their safety for human consumption.
What is ListShieldTM?
ListShield™ (formerly LMP-102) is an all-natural product that contains six
different bacteriophages isolated from the environment. The
phages in ListShield™ have not been altered or manipulated in any
way. The preparation specifically targets a foodborne bacterium
called Listeria monocytogenes which kills approximately 500
people each year in the USA alone. Applying ListShield™ to
various ready-to-eat foods significantly reduces (usually by
99-100%) their contamination with this potentially deadly
bacterium; thereby, increasing their safety for human
consumption. See product
page or contact Intralytix
for more information.
What is EcoShieldTM?
EcoShield™ (formerly ECP-100) is an
all-natural product that contains three different bacteriophages
isolated from the environment. The phages in EcoShield™ have not
been altered or manipulated in any way. The preparation
specifically targets a foodborne bacterium called Escherichia
coli O157:H7, which causes approximately 62,000 foodborne illnesses each year in
the USA alone. Applying EcoShield™ to various ready-to-eat foods
significantly reduces (usually by 99-100%) their contamination
with this potentially deadly bacterium; thereby, increasing
their safety for human consumption. See
product page or
contact Intralytix for more
information.
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Do ListShieldTM
or EcoShieldTM alter the taste or smell of treated foods?
ListShield™ and EcoShield™
do not alter the general composition of foods, and
they do not produce any detectable adverse organoleptic changes;
i.e., it does not alter the taste, odor or color of foods
treated with it.
Do ListShieldTM or EcoShieldTM
extend the shelf-life of treated foods?
ListShield™ and EcoShield™ do not affect the shelf-life of treated food. In
other words, they do not extend or shorten the shelf-life of
treated foods.
How are
ListShieldTM
and EcoShieldTM
different from the chemicals currently used to
improve food safety?
ListShield™ specifically kills only
Listeria monocytogenes and EcoShield™ specifically kills only
Escherichia coli O157:H7– both deadly foodborne pathogens – on
foods, without affecting the beneficial “good” bacteria commonly
found on and in various foods. Using phages to target pathogenic
“bad” bacteria in our foods without affecting the beneficial
bacteria is a breakthrough in the food safety area. We all live
in a very complex environment, in which bacteria play very
important roles. Although there are some bacteria that can make
people sick or even kill them (including L. monocytogenes and
E.
coli O157:H7, which both can cause human illness and can kill
infected people, particularly children and pregnant women), most
bacteria are actually beneficial and without them life would not
be possible on Earth. Some examples of beneficial bacteria are
those found in yogurt and other healthy foods, which help us to
digest various foods, synthesize some important nutrients,
enhance immune system function, etc. Traditional approaches for
dealing with potentially pathogenic bacteria include using
antibiotics, irradiation, chemicals, and heat to reduce their
presence. While those approaches effectively kill bacteria, it
is important to understand that we cannot eliminate all
bacteria. In fact, it is against our best interests to attempt
to do so and herein lies the problem: a lack of commercial
products that specifically target and kill pathogenic bacteria
without disturbing the normal, beneficial bacteria in the
environment and body. Mother Nature has such a tool, which she
has been using for billions of years to maintain the proper
balance of various bacteria in the environment. They are bacteriophages, which, in a well-balanced predator-prey
relationship, have been keeping bacteria in check for millennia.
ListShield™, EcoShield™, and similar pathogenic bacteria
targeting, bacteriophage-based natural products can dramatically
improve the safety of our foods while maintaining their
beneficial bacterial content.
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