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Rewriting Life

Nanobiotic Lifesavers

Synthetic peptide rings can self-assemble into antibiotic nanotubes that puncture deadly bacteria.

Nanotubes that construct themselves out of peptide rings may offer an effective new weapon against antibiotic-resistant bacteria and the threat of incurable diseases.

Resembling a molecular donut, a 2.5-nanometer ring of customized amino acids sinks into the cell wall of a staphylococcus aureus bacterium, one of the antibiotic-resistant strains responsible for life-threatening hospital infections.

Millions more of these sticky, donut-shaped “cyclic peptides”-each a looped chain of amino acids-enter the bacterium’s gelatinous cell wall. They chemically gravitate toward each other and assemble themselves into elongated tubes, like stacks of tiny tires embedded in the cell membrane.

Single peptide tubes then pierce the membrane. Groups of adjacent tubes work together to open even larger, gaping pores in the cell wall. Within minutes, numerous holes kill the bacterium by disrupting the electrical potential of its membrane, effectively shutting down the cell’s interior machinery.

Lethal Injectors

Developed by a team led by M. Reza Ghadiri at the La Jolla-CA based Scripps Research Institute, these nanobiotic lifesavers may be able to kill even the most drug-resistant bacteria, while sparing animal cells.

The World Health Organization estimates the total cost of treating all hospital-borne antibiotic-resistant bacterial infections is around $10 billion a year.

While human trials are two to three years away, the group has tested their synthetic, self-assembling peptide nanotubes in mice, knocking out deadly infections of methicillin-resistant staphylococcus aureus. The peptides also show promise in treating a wide variety of deadly bacteria strains, including Escherichia coli, pseudomonas aeruginosa and Enterococcus faecalis. They may eventually prove effective against fungal and parasitic infections.

Ghadiri’s peptide rings, composed of a novel alternating pattern of naturally occurring and synthetic amino acids, have amino acid side chains that face outward from the “donut” and react to the environment.

These “sensor” molecules can be quickly reconfigured in the lab to adjust how the peptides work. “We can produce 100,000 variants in about two weeks,” Ghadiri says. That flexibility should ultimately let drug makers choose which bacteria they target, control how the peptides insert themselves into the membrane and self-assemble, and minimize the toxicity to animal cells in the infected host.

Dr. Tomas Ganz, an experimental pathologist at UCLA medical school, says the work of Ghadiri’s group represents a potential new class of molecular smart weapons. However, he cautions that these substances are not yet medications. “They must be economical to produce and prove effective and nontoxic in humans,” he says.

Longer Shelf Life

The speed with which they work and the peptides’ novel structure should make it harder for bacteria to develop resistance, Ghadiri says, paving the way for a new class of drugs with a longer shelf life. But, he warns, “no one should ever underestimate the adaptability of bacteria.”

Cyclic peptides have been investigated for years. Many natural peptides defend against microbes in animals and plants. Other drugs based on cyclic peptides, such as Bacitracin, are commonly used as topical antibiotics.

Scripps researchers first stacked cyclic peptides into nanotubes in 1992. At first, they hoped to create nanoscale “test tubes” for biochemical research. But when they noticed the tubes’ membrane activity in 1994, they quickly refocused their discovery on the treatment of multidrug-resistant bacteria.

As a result, Ghadiri feels fortunate “that in a relatively short period of time our work may be leading to something useful for millions of people.”

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