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Promising Antibiotic Candidate Identified

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Science  17 Dec 1999:
Vol. 286, Issue 5448, pp. 2245-2247
DOI: 10.1126/science.286.5448.2245

The ever-increasing resistance of pathogenic microbes to antibiotics has raised the specter of a “postantibiotic era” in which doctors are powerless to treat many bacterial infections. Even vancomycin, a longtime antibiotic of last resort, appears to be losing its punch. Now researchers have come up with a possible replacement—one that they say could lead to a whole new generation of antibiotics. It's not a brand-new invention, however. In fact, it has been used as a food preservative for over half a century.

The compound, nisin, is a peptide—a small proteinlike molecule—produced by Lactococcus lactis, a bacterium that can turn milk sour, to kill its competitors. Microbiologists have known for decades that nisin is an effective killer, but they never knew exactly how it worked. On page 2361, a Dutch-German team provides an answer. They show that the peptide latches onto a molecule on many bacterial cell membranes known as Lipid II—the same target used by vancomycin. The result suggests that nisin, or derivatives of it, could one day replace vancomycin as a broad-range antibiotic. And because nobody has ever found a bug that is resistant to nisin, the researchers hope that nisin and related compounds might trump the problem of bacterial resistance. “This looks like a very significant contribution,” says biochemist Norman Hansen of the University of Maryland, College Park.

Nisin is only one of many antimicrobial peptides that have recently caught researchers' interest; others have been isolated from frog skin, insects, and plants, for instance. Most kill bacteria by sticking to and punching a hole in their fatty cell membranes. Some studies suggested that nisin might work the same way. But whereas large quantities of the other peptides are needed to do the job, limiting their usefulness, nisin always stood out because it is effective at concentrations up to 1000 times lower, making it a popular preservative for dairy and many other products. “There has always been this question about why nisin is different,” says Tomas Ganz, who studies antimicrobial peptides at the University of California, Los Angeles.

Other work had suggested that might be because nisin has a different mode of action: Like vancomycin, it might bind to Lipid II, which is a precursor of the bacterial cell wall, a tough protective layer that lies outside the membrane. The binding would rob bacteria of their ability to build cell walls, eventually killing them.

The new study, from biochemists Eefjan Breukink and Ben de Kruijff of Utrecht University in the Netherlands, together with colleagues at three other institutions, indicates that both explanations are in fact partially correct. For example, the researchers found that nisin resembles magainin, a peptide antibiotic derived from frogs, in that it kills Micrococcus flavus bacteria within a few minutes by forming pores in the cell membrane. But they also found that vancomycin interferes with nisin's ability to make these holes, presumably because it competes with the peptide in binding to Lipid II. Conversely, when the researchers fused the bacterial membranes to artificial membranes loaded with extra Lipid II, nisin's pore-forming power was bolstered.

Apparently, says Breukink, Lipid II is a special key that nisin uses to punch its deadly holes—a key that other antimicrobial peptides lack. He does not yet know exactly how Lipid II helps nisin form pores. But he is sure that the peptide attaches to a different part of the lipid than vancomycin does, which may explain why bacteria have become resistant to vancomycin but not to nisin.

Now that researchers know that Lipid II is such an Achilles' heel for bacteria, they can try to devise a whole range of compounds that exploit it. The low doses needed would reduce the risk of side effects, Ganz says, and could help make the drugs economically feasible. And by tinkering a little with the nisin gene, researchers could easily produce many slightly different derivatives, for instance if resistance arises. “This holds the promise of giving access to huge numbers of antibiotics through relatively simple means,” says Hansen.

But many hurdles will have to be overcome. For one, nisin can only kill Streptococcus, Staphylococcus, and other so-called gram-positive bacteria. Another problem is that peptides have a short lifetime in the body and a higher risk of triggering allergic reactions than conventional antibiotics have. Still, the new study may help motivate the pharmaceutical industry to overcome such obstacles, says Hansen: “They just have never recognized the potential of these antimicrobial peptides.”

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