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.

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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.

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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.”

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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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