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Planning for the Day
Antibiotics Fail
March 13, 2000
By Alex Daniels
adaniels@washtech.com
In a few months, scientists at Intralytix will begin scraping
the bottom of Baltimore’s Inner Harbor for what they hope is a
cure for infections. While most medical researchers synthesize
new therapeutic compounds in sterilized laboratory clean rooms,
the scientists at this small Baltimore startup hope to harvest
naturally occurring predators of bacteria known as
bacteriophages, or phages.
That means the company must scour the dank, grimy nooks that
bacteria call home, whether it is the harbor, or the sewers at
the nearby University of Maryland Baltimore campus.
 What the
company scoops up could keep the practice of medicine from
getting drop-kicked back into the days before the penicillin
revolution. That’s because bacteria are quickly adapting and
developing resistance to antibiotics.
“All these things modern medicine is so proud of,” such as
chemotherapy and organ transplants, “will become impossible if
bacteria develop antibiotic resistance,” says Alexander
Sulakvelidze, who along with Torrey Brown, a former Maryland
Secretary of Natural Resources, and five others, founded
Intralytix. “That will mean a setback of modern medicine to the
pre-antibiotic era, which is very alarming,” Sulakvelidze says.
The two-year-old company wants to develop phages for industrial
uses, such as wiping out microorganisms in food processing
plants and hospitals, and for therapeutics. Intralytix is at a
very early stage in its development, but so far has secured a
sponsored research arrangement with the University of Maryland
and a similar agreement with “one of the world’s largest food
processors” - although it won’t identify the company.
While declining to talk specifically about the company’s budget,
Sulakvelidze says Intralytix has spent more than $1 million
since its inception. In the next two years the company hopes to
have a product on the market to mitigate bacteria contamination
in industrial facilities, but clearing the Food and Drug
Administration regulatory process for use in humans is likely to
take much longer.
That’s not to say the idea of using phages in humans is new.
People have been ingesting them to fight bacteria for almost a
century. In fact, starting in the late 1930s a factory in the
former Soviet Republic of Georgia pumped out phages by the ton
to be used in Red Army medical kits, where they were used to
combat E.coli, dysentery and salmonella infections.
Phages’ ability to destroy bacteria was first discovered in the
early 1900s, but took a backseat in the fight against disease
when antibiotics were discovered. But phages never fell out of
favor in the Soviet bloc, where they were manufactured at the
Eliava Institute, in Tblisi, Georgia.
Now, Intralytix, which funds research activities at Eliava and
two other U.S. companies, is trying to usher phages into
widespread use in this country.
Think of phages as the hydrogen bomb in the war against
bacteria. The self-replicating viruses, which have alien-like
tails and clunky heads, are wired to reproduce inside of
specific bacteria and kill it, but leave all mammal and plant
cells unscathed.
“They’re really cute,” says Sulakvelidze, admiring a slide of
the tiny killers.
Another Maryland company that is hoping to wipe out
microorganisms. But Antex Biologics, based in Gaithersburg, is
taking a different approach. Instead of using phages, the
company is undertaking pre-clinical trials of compounds that
modulate bacteria’s virulence, essentially rendering the
organisms toothless but not killing them.
“New therapies are needed,” says Theresa Stevens, Antex’s vice
president of corporate development, “because the currently
marketed pharmaceuticals are meeting a high level of resistance
to the antibiotics that are out there.”
Stevens says that Antex considered testing phages but decided
against it.
“It still has to be evaluated in humans, but the idea certainly
has merit. It seems to be coming into favor a little bit more
recently,” Stevens says.
Last month, the National Institute of Allergy and Infectious
Disease signaled it was interested in bacteriophages when it
announced that it would give challenge grants, starting at
$25,000, to companies involved in phage research. Specifically,
the institute wants to determine if phages will kill
Enterrococci, the leading cause of hospital infections in the
United States. The bacteria are demonstrating increased
resistance to Vancomycin, an antibiotic.
Carl Merril, chief of the Laboratory of Biochemical Genetics
at the National Institute of Mental Health, has helped advance
the field, beginning with a paper on phages he authored in 1996.
Merril, along with colleagues at the National Cancer Institute,
continues to work with phages, manipulating them so they target
a wider range of bacteria and stay in the body for a longer
period of time.
Getting a handle on the market for new classes of
bacteria-fighting compounds is difficult. Phage Therapeutics, a
company based in Washington state, says that there is a $35
billion market for phages.
“This is not something with for which there is a very
well-established market,” says Steven Fritz, associate vice
president for research and development at the University of
Maryland.
Intralytix has a two-year arrangement to pay scientists at
the university up to $760,000 to work on phages. Fritz says that
the university is negotiating to enter into a licensing
agreement with the company, which would pay the school royalties
should a product come to market. In addition to the domestic
competition and the uncertainty of getting a compound through
clinical trials, Fritz says it is possible that phages’ long
history of use could trigger patent actions, in the U.S. and
Europe.
“Because bacteriophages have been used so extensively in Eastern
Europe, there may be some intellectual property prior art out
there,” Fritz says. “We don’t know how big a factor that is.”
Sulakvelidze, who served as a deputy director of health in
Georgia before emigrating several years ago, has worked
extensively with Eliava labs and says the company’s continued
collaboration with the Georgians will help them in the event of
an intellectual property dispute.
"I do not think phages as they have been used in Georgia will
be acceptable to the FDA,” says Sulakvelidze, explaining that
the labs there lack the oversight and funding to process
purified, stable phages. “We will take the responsibility for
shepherding them through the regulatory process in the United
States.”
If the company’s phages do come to market, Sulakvelidze
doesn’t expect them to totally replace antibiotics. While
broad-spectrum antibiotics can wipe out a multitude of bacteria,
phages are very specific to particular strains, and have to be
cultivated to match their target.
But, Sulakvelidze says it is unlikely that phages will be
outwitted by their prey.
“As opposed to antibiotics, which are human-synthesized, with
phages Mother Nature is working against Mother Nature, and this
is a never-ending process,” he says. “Mother Nature will always
produce a superphage that will be active against a resistant
bacteria.”
Comparing bacteriophages to antibiotics:
Phages
Advantages:
- Specificity. They affect the only the targeted bacteria,
avoiding the possibility of developing secondary infections
- Side effects. Only few side effects, such as liver pain
have been reported.
- Dosage. Phages self-reproduce as long as corresponding
host bacteria are present, so the need to repeatedly
administer the phage is greatly reduced.
- Development time and expense. Selecting a new phage
frequently can be accomplished in days and production is
relatively simple and cheap.
Disadvantage:
- Specificity. Because of the high specificity of phages,
the disease-causing bacterium has to be properly identified
before phage therapy can be started.
Antibiotics
Disadvantages:
- Specificity. Antibiotics can affect not only the targeted
pathogenic microorganisms, but also normal cells. This can
lead to secondary infections.
- Side effects. Multiple side effects, including yeast
infections, intestinal disorders and allergies.
- Dosage. Repeated administrations are often needed.
- Development time and expense. Developing a new antibiotic
can take years and millions of dollars.
Advantage:
- Specificity. Antibiotics can be used without knowing the
exact identity of the disease-causing bacteria.
Source: Intralytix
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