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Infectious Arms Race
Forging new weapons against resurgent bacterial killers
BY THOMAS HAYDEN
Think your job's frustrating? Try a tour of duty in the war
against bacteria. Stephen Sanche, an infectious disease
specialist in Saskatoon, Canada, has been on the front lines for
12 years now, but the work somehow keeps getting tougher. Take
one patient, a 78-year-old retiree with a spinal infection.
After two weeks on multiple antibiotics, he was in worse shape
than ever. It took 10 weeks and three more powerful antibiotics
for him to improve. "The first antibiotics should have been
effective," Sanche says. "But every year we're seeing more
bacteria more resistant to treatments that worked well when I
started."
More than seven decades after a microbe first succumbed to
penicillium mold in Alexander Fleming's petri dish, we weren't
supposed to be worrying about bacteria anymore. But the bugs are
back–with a vengeance. Hospitals, nursing homes, and day-care
centers have become the haunts of deadly pathogens, many of them
newly impervious to standard treatments. In this, the age of
high-tech medicine, the pneumococcus bacterium alone kills some
40,000 Americans every year. And out in the streets,
drug-resistant strains of old enemies like tuberculosis and
gonorrhea are staging a major resurgence. In his 1992 book The
Antibiotic Paradox, Tufts University microbiologist Stuart Levy
warned of a looming antibiotic resistance crisis. A decade
later, Levy says, it is so much worse he's had to write a new
edition. "I don't think calling [antibiotic resistance] a
national security issue is overstating it. The bottom line is,
we need new drugs."
Scientists are answering that call, turning to advances in
genomics, molecular biology, and chemical synthesis to develop
the first new antibiotics in a generation. First they worked out
the genetic tricks that bacteria use to outsmart drugs–enzymes
to chop antibiotics into harmless pieces, molecular pumps to
squirt invading chemicals right back out again. Researchers are
now fighting back with tricks of their own, including chemicals
that gum up the protective enzymes and molecular corks to block
bacterial pumps.
Zappers. Drug developers are also combing bacterial
genomes–their genetic parts lists–for new molecular soft spots.
Chemists are sorting through hundreds of thousands of chemical
compounds, looking for potential bug zappers. In April 2000, Zyvox–approved for major hospital-acquired infections–became the
first entirely new addition to the antibiotic arsenal in 35
years. Another half-dozen drugs are in clinical trials, and labs
everywhere are finding novel ways to attack bacteria.
Of all the traditional antibiotics, only the fluoroquinolones
(think Cipro) are artificial compounds. We've co-opted the rest
from microbe-killing compounds found in nature, where bacteria
have had eons to develop ways of protecting themselves. So
chemists are now engineering their own molecules, hoping that
bacteria will be stymied by unfamiliar toxins.
At the Scripps Research Institute in La Jolla, Calif., Reza
Ghadiri is creating doughnut-shaped chemicals called cyclic
peptides. The molecules insert themselves into bacterial cell
membranes, causing fatal leaks. Compared with traditional
antibiotics, the peptides should be harder for bacteria to shrug
off, not only because they are fresh weapons but also because
they attack a complex structure rather than a single enzyme,
Ghadiri says. His team already has successfully cured mice of
staph infections with these chemicals. "It's working faster and
better than we dreamed," he says. Next step: handing the
research off to a drug development company.
Remember Jonathan Swift's beleaguered fleas? "A flea / Has
smaller fleas that on him prey; / And these have smaller still
to bite 'em; / And so proceed ad infinitum." Bacteria, too, have
their pests: tiny viruses called phages that can be wonderfully
adept at invading bacteria and bursting them from within. Early
attempts to fight bacteria with their viral fleas showed
promise, but when penicillin became widely available in the
early 1940s, "phage therapy" faded in the West. (Soviet
scientists stuck with it, and even now one can buy phage over
the counter in the Republic of Georgia.) At the University of
Maryland, epidemiologist Alexander Sulakvelidze is taking a
second look at the bacteria killers. "We're trying to bring the
old technology to a state-of-the- art biotech level," says
Sulakvelidze, who once worked at the Georgian institute that did
Soviet phage research. With the biotech company Intralytix,
Sulakvelidze hopes to start human trials soon.
If you don't relish the thought of swallowing a dose of
virus–or of old Soviet science–you may prefer Vincent
Fischetti's approach. The Rockefeller University microbiologist
has isolated the enzyme that phages use to chew through
bacterial cell walls and, in a study published last week in the
journal Science, has shown it can obliterate pneumococcus in
mice. Fischetti foresees nasal sprays based on the enzyme that
could deal a pre-emptive blow to dangerous germs that lurk in
the nose and throat, waiting to cause, among other things, some
10 million childhood ear infections a year. Trials could start
next year, he says. "The enzymes are ready to go."
Heeding his own call for new drugs, Levy also aims to stop
infection before it starts, by zeroing in on bacterial genetics.
A single regulator protein controls 75 to 80 different genes
that enable bacteria like salmonella, shi-gella, and E. coli to
release toxins and fight antibiotics. Because the bugs often
infect surgery patients, notes Levy, a regulatory inhibitor
could be given to disarm any invaders before the first cut. "We
can't always keep bacteria out of the body," says Levy, "but we
may be able to keep them from causing any harm." Several
promising inhibitors have been identified, he says, but clinical
tests are still years away.
No matter how many new drugs are brought to the battle,
evolutionary biologists warn that we'll never win the war with
bacteria outright. Because bacteria adapt so readily, says Paul
Ewald of Amherst College, "no matter what chemicals we throw at
them, they'll find a way around it" in the end.
Life cycles. Yet evolutionary thinking also points to ways of
staving off defeat. One is resisting the temptation to prescribe
antibiotics "just in case"–witness the recent run on Cipro.
Another, says Stephen Palumbi of Harvard University, is taking a
lesson from farmers, who are fighting the parallel problem of
pesticide-resistant insects. Just as farmers are learning to
alternate pesticides so the quarry never gets too comfortable
with any particular one, doctors might rotate antibiotics as
they treat infections. Ewald also suggests paying more attention
to the life cycles of disease bacteria. Syphilis, for example,
is infectious only for the first few months but causes most of
its damage later on. So doctors could reserve their most
precious antibiotics–those that remain potent–for later stages,
when resistant bacteria can't spread.
But ultimately, says Ewald, we'll have to learn to live with
bacteria. Call it a truce, rather than a victory. "Our goal," he
says, "should not be to eradicate pathogens but to favor mild
strains." Cholera in South America shows how it can happen. In
countries with substandard water treatment, cholera remains a
killer. But in Chile, with its modern water treatment
facilities, the bug has become mild–almost domesticated. The
reason? Unable to spread through contaminated water, bacteria
that made people too sick to get out of bed never got a chance
to infect anyone else. Only milder strains that could spread as
their relatively healthy hosts went about their business could
flourish.
By changing our own behavior, Ewald says, we can in essence
convince some of our most virulent pathogens to change theirs.
He's not talking about 21st-century science; strategies as
simple as staying at home–and away from the kids–when you feel
too sick to work can help coax pathogenic species to evolve into
kinder, gentler versions of their former selves. "Up until now,"
says Ewald, "evolution has been part of the problem. But it can
also be part of the solution."
Phage cycle - Click image to enlarge
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