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New Antibiotic Packs Extra Punch

Scientists design compounds that poke deadly holes in bacteria

WEDNESDAY, July 25, 2001 (HealthDayNews) -- Doctors desperate for a new weapon in the battle against antibiotic-resistant bacteria soon could have a tiny but deadly addition to their arsenal.

Scientists at the Scripps Research Institute in California have developed a new class of antibiotics called "self-assembling peptide nanotubes." The compounds use rings of microscopic amino acids that form tubes to punch through the surface of a bacterium.

"If you poke holes with nanotubes on a living membrane, you can kill the cells," says lead research author M. Reza Ghadiri. "This is a very new approach to drug design."

The discovery could lead to a new generation of antibiotics that bacteria would have a hard time developing immunity to, experts say.

Ghadiri and his colleagues describe the compounds in tomorrow's issue of Nature. They've designed what's called a "cyclic peptide" made of amino acids, the building blocks of natural proteins found in our bodies. But their design is a shape that nature has never produced -- a flat ring structure that can attach itself to the cell membrane of a pathogen and punch through it.

And he says the nanotubes can be designed to distinguish between friend and foe, so they attack only invading pathogens.

Ghadiri says, "You need to be very selective," because a nanotube will only form if certain molecules are on a membrane surface. On a cell membrane with the characteristics of, say, an animal cell, "it won't touch it. It won't form nanotubes, it won't kill it," he says.

"There's a difference in bacterial and mammalian cells, and these molecules can sense that on their own and decide whether this is the target or not. It sounds like science fiction, but it's true," Ghadiri says.

"Very quickly, if they're [attracted to something on the surface], the tube is formed and kills the cell," says Ghadiri. "They are very fast-acting agents, unlike most antibiotics on the market. … Ours kills them on contact."

Ghadiri says the nanotubes killed antibiotic-resistant bacteria in the laboratory, but the true test is whether it will work in a living organism. When mice infected with methicillin-resistant Staphylococcus aureus were given a single injection of the nanotubes, the infection cleared completely, while all the mice that received a placebo died, he says.

"These infections are major components of the annual 2 million hospital-acquired infections in the United States, which are increasingly becoming resistant to therapeutics that are available," says Ghadiri.

Conventional antibiotics operate like a lock and key, where drugs hook onto a specific receptor on the bacterium.

Antibiotic resistance develops when the bacterium mutates, changing the target receptor.

"If you change one of the teeth on the lock, [the key] won't fit anymore, and there's only so much you can change about the key," says Ghadiri.

Dr. Tomas Ganz, director of the Will Rogers Pulmonary Research Laboratory at the University of California School of Medicine, in Los Angeles, calls the nanotubes "a very clever design."

"With this kind of antibiotic … the target is the membrane of the bacterium, so there isn't one specific molecule. It's the entire structure that's the target," says Ganz.

"To prevent the antibiotic from working would probably require a very major change in the structure of the membrane. [It] is much harder for the bacterium, both to accumulate the mutations necessary to change the membranes in such a major way and to still preserve the function of the membrane," he says.

"The negative impact on the bacterium of having to change its membrane may be much greater than having to change only one molecule that's the target of the older antibiotics," so it could slow the onset of resistance to this new class of antibiotics, says Ganz.

The researchers have yet to conduct animal studies of other antibiotic-resistant bacteria, and Ghadiri says they also want to find out whether the nanotubes have anti-fungal properties or whether they can attack certain forms of cancer.

But while the potential for new drugs that could save human lives is great, Ghadiri says these compounds are several years from any human application.

Besides testing in other animals, Ganz says the researchers will need to find an easier way to prepare these antibiotics, which currently require a complex and expensive production process.

"I think we need them badly," says Ganz. "It's possible that in the short run, we can prolong the effectiveness of the existing antibiotics by using them more cautiously. But the more choices we have, the better."

What To Do: Get a closer look at the nanotubes at the Scripps Research Institute. And find out more about antibiotic resistance from the Centers for Disease Control and Prevention or the U.S. Food and Drug Administration.

SOURCES: Interviews with M. Reza Ghadiri, Ph.D., professor, Department of Chemistry and Molecular Biology, Scripps Research Institute, La Jolla, Calif.; Tomas Ganz, M.D., Ph.D., professor of medicine and pathology, director, Will Rogers Pulmonary Research Laboratory, University of California, Los Angeles, School of Medicine, Los Angeles; July 26, 2001, Nature
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