New Antibiotics Take Poke at Bacteria

Imagine a roll of LifeSavers. Now, mentally shrink that stack of candy rings to a few nanometers in length, making it smaller than a cell.

That image offers a sense of the unusual structure behind a potential new class of antibiotics developed by M. Reza Ghadiri of the Scripps Research Institute in La Jolla, Calif., and his colleagues. In the July 26 Nature, the investigators report that their nanotubes swiftly kill a wide range of bacteria in both test tubes and animals. The structures helped mice stave off normally lethal bacteria that are resistant to a traditional antibiotic, the Scripps researchers found.

At the structural heart of the drugs are rings, called cyclic peptides, that are composed of either six or eight amino acids. Under the proper conditions, such as within bacterial membranes, these rings assemble into hollow tubes. The tubes punch holes in the membranes, quickly killing the microbes.

The tube-forming rings, dubbed nanobiotics, combine the natural and the unnatural, says Ghadiri. Every amino acid can come in two forms, one the mirror image of the other. The left-handed, or L, version occurs naturally, but scientists can synthesize the right-handed, or D, counterpart. By alternating D and L amino acids, Ghadiri’s team synthesized short strings of amino acids that form into stable rings, which, in turn, can interlock with each other into stacks.

“It’s a very clever structure that advances the field significantly,” says Tomas Ganz of the University of California, Los Angeles, who studies antimicrobial peptides.

The choice of amino acids determines the conditions in which the rings stick together. By using positively charged amino acids, Ghadiri’s team made the nanotubes assemble only in the negatively charged membranes of bacteria. Within the neutral membranes of mammalian cells, no assembly should occur.

In test-tube experiments, Ghadiri’s team found that nanobiotics can kill a variety of disease-causing bacteria while leaving red blood cells unharmed. Without obvious side effects, the nanotubes protected animals infected with an antibiotic-resistant strain of Staphylococcus aureus. Each year, such bacteria infect more than 2 million hospital patients in the United States.

Ghadiri suggests that membrane-destroying drugs, such as his nanobiotics, may be more difficult for bacteria to defeat than current antibiotics. Those drugs typically target a specific molecule within bacteria. Microbes eventually develop resistance by altering the shape of the targeted molecule or by somehow keeping the drugs away from it.

“Our hope is that this class [of antibiotics] would have a longer longevity,” says Ghadiri.

“The bacteria have to do more to become resistant.” What’s more, he adds, by changing amino acids in the peptide rings, scientists can create countless variations on the nanobiotics and further delay resistance.

Although his team so far has used only injections to administer the peptides, Ghadiri is optimistic that the compounds can be delivered in pills. At this point, however, Ghadiri says he and his colleagues have done about as much as they can to establish the promise of their peptides. Ganz agrees, adding that to become drugs, the compounds need testing and development far beyond the means of a single research team.

“We’d be delighted to work with the pharmaceutical or biotech industry,” says Ghadiri. “These are relatively small molecules that can be synthesized very easily, very quickly, and on large scales.”

If the bacteria-thwarting nanotubes ever do make it to pharmacy shelves, they’ll seem like LifeSavers in more ways than one.