Here you go George, MAKE SURE YOU SCROLL DOWN TO INTERVIEW WITH SCANNON
10/21/98
The Orange County Register
MORNING
Research into new antibiotics has come roaring back, with at
least 27 candidates now in development, according to the
Pharmaceutical Research and Manufacturers of America. But don't
expect to get a prescription soon. Most are still years away from
market approval.
After about a 10-year hiatus in the search for new antibiotics,
many of the major drug companies _ Schering-Plough, Bristol-Myers
Squibb, Pfizer and Pharmacia & Upjohn _ are now sinking millions
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into antibiotic development. Small biotech companies also are
players in the race.
TD Spurring them on is the rapid increase in bugs that can fight
off some of the more than 100 different antibiotics now on the
market. While most bacterial infections still are treatable, a few
strains are able to resist everything modern medicine can throw at
them.
Multiple-drug-resistant strains include some forms of
tuberculosis as well as streptococcus pneumoniae, the cause not
only of pneumonia but also of childhood ear infections and
meningitis. Hospitalized patients recovering from surgery also are
prey to a common intestinal microbe, enteroccocci, that has
developed resistance to even vancomycin, an intravenous antibiotic
that is the strongest in the medical arsenal. The bacteria can kill
if it gets into the bloodstream.
The organism is "essentially untreatable right now," said John
Fiddes, vice president of research and development at IntraBiotics
in Mountain View, which is about to launch a second-stage trial of
a product that might wipe out the bad strain of enteroccoci while
it still lies harmless in patients' intestines.
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While some researchers are tinkering with existing antibiotics
to try to make them stronger, others are using the tools of modern
genetics to look for entirely new classes of antibiotics. That way,
they believe, they can foil the defenses many bacterial strains
have developed.
Winners of the race would break into what is a $20 billion
worldwide market for antibiotics. Simply finding a replacement for
vancomycin could be a $1 billion opportunity in the United States
alone, analysts say.
Even so, the race won't be won quickly. The research and tests
needed to bring a new drug to market can take 10 years or more.
"They're not going to be out in this decade," said Stuart Levy,
director of the Center for Adaptation Genetics and Drug Resistance
at Tufts University School of Medicine.
And that worries him.
"In the short run, we need much more attention to a more
prudent use of antibiotics," said Levy, who has written a book and
articles on how the overuse of antibiotics by humans and the
widespread use of antibiotics in livestock feed have aided the
evolution of superbugs.
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Overuse of antibiotics can aid bacterial resistance when only
some cells are killed, sparing bacteria with resistance genes. The
survivors then proliferate and pass their resistance along to other
cells.
Microbes have learned several ways to beat the drugs. They can
secrete an enzyme that neutralizes antibiotics, strengthen their
cell walls to keep drugs out or activate an internal "pump" to spit
out those antibiotics that do breach their cell walls.
"About 10 or 12 years ago, a lot of companies decided to get
out of antibiotics," said Francis Tally, executive vice president
of scientific affairs for Cubist Pharmaceuticals Inc. in Cambridge,
Mass. "There was an intellectual arrogance that we'd already
developed all the drugs we need. The only group that didn't listen
was the bacteria."
As the bacteria have gotten more sophisticated, so have the
scientists.
The traditional method of searching for antibiotics _ sometimes
dubbed "search the dirt" _ was to look for naturally occurring
organisms that appeared to fight off bacteria. The first
antibiotic, penicillin, was discovered that way in 1928 when
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Alexander Fleming found the property in a common bread mold.
In more recent years, pharmaceutical companies would send
employees out to exotic climes to bring back soil samples. The dirt
then would be screened for potentially helpful organisms.
In the 1980s, researchers began trying to build their own
antibiotics by combining molecules. But those efforts were hampered
by a limited understanding of the microbes' genetic profiles. That
changed in the mid-1990s, when DNA sequencing took off. The
complete gene set of some bacterial strains now is known.
"Now, designing antibiotics because we know the genomic
sequence of bacteria becomes possible," said Dr. Patrick Scannon,
* chief scientific and medical officer at Xoma Corp in Berkeley.
Based on that knowledge, researchers combine chemicals to find
compounds that will hit the right "targets" in a bacterial cell, a
process known as combinatorial chemistry. "With the search-the-dirt
method, you might come up with 1,000 molecules to test," Scannon
said. "Now combinatorial chemistry gives us a million molecules."
New rapid methods of screening those molecules to see if they
have any effect on a cell's DNA means that many more potential drug
compounds are available to researchers.
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"The good news is that our chances of finding something that
will actually work is markedly improved," Scannon said.
* Even so, a potential new drug from Xoma with antibiotic
capability was discovered the old-fashioned way: Scientists at New
York University knew that white blood cells can kill bacteria, so
they set about finding how they do it.
* Eventually they isolated a human protein. Xoma then cloned it
and made it into a formulation called Neuprex. Human trials of the
drug on children afflicted with an often deadly blood infection
called meningococcemia have proved promising. The drug also shows
an ability to boost the strength of existing antibiotics.
Another San Francisco Bay area company, MicroCide, was formed
in 1992 specifically for finding solutions to the resistance
problem. While it does not yet have a product in human testing, it
is developing a compound that might wipe out the "pump" some
bacterial strains have developed to eject antibiotics. It also is
working with Pfizer to design new classes of antibiotics.
Closer to approval is a drug from the French company
Rhone-Poulenc Rorer. Called Synercid, the drug is the first
injectable form of a class of antibiotics called streptogramins.
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But Synercid has been used only in animals so far, and the FDA
still is reviewing it for use in humans.
Other promising possibilities for new classes of antibiotics
include a Pharmacia & Upjohn drug called linezolid and an
intravenous product from Shering-Plough called Ziracin. Both are in
final-stage human trials.
Meanwhile, other companies are working on new vaccines that
might prevent disease, eliminating the need for antibiotics. |
