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Synthetic Peptide Shows Promise as Antibiotic

By Michael Vatalaro

For every action there is an equal and opposite reaction. Researchers develop an antibiotic drug; bacteria develop resistance to it. Unlike in physics, in the world of infectious diseases the reaction — bacterial drug resistance — takes place slowly, over time. But it does occur. In the 50 years since the advent of penicillin, many bacterial diseases that doctors thought were beaten have reemerged with a vengeance, largely immune to penicillin and its close relatives. In Thailand, more than 98 percent of new gonorrhea cases do not respond to penicillin.

Creating new antibiotics gets us ahead of the "bugs," but only for a while. Until now, nearly all antibiotics have come from natural sources, limiting the number of potential drugs. The next logical step is either to attack the microbes' mechanism of resistance, making the old drugs effective once again, or to design a chemical that evades resistance. Now researchers using concepts from protein folding studies, combined with the structural analysis of organic molecules, have developed a synthetic antibiotic peptide — a chain of amino acids — that might evade microbial resistance.

Using forms of amino acids not found in nature known as beta-amino acids, researchers supported by NIGMS synthesized a molecule that shows remarkable potency against both gram-negative and gram-positive bacteria. Most antibiotics kill one class of bacteria or the other, but not both. The new molecule also kills drug-resistant strains of Enterococcus faecium and Staphylococcus aureus, bacteria feared by doctors and hospital staff. Dr. Samuel H. Gellman, a professor of chemistry at the University of Wisconsin, Madison, and Dr. Bernard Weisblum, a professor of pharmacology there, published the work in April in the journal Nature.

Gellman's beta-peptide is structurally similar to a class of natural antimicrobial peptides called magainins. These peptides appear to defend biological borders, such as your skin, from invading bacteria by punching holes in the microbes' membranes, killing them.

Legend has it that Dr. Michael Zasloff, one of the first researchers to describe magainins, looked down into the murky water of a tank that contained a group of frogs that he used in his research at NICHD. Zasloff realized that all of the frogs had exposed sutures on their backs from recent surgery, yet none of the frogs showed any signs of infection. He wondered what was protecting the frogs from infection as they swam in a microbial soup. The answer turned out to be magainins.

The exact mechanism magainins use to disrupt microbial membranes is unknown. However, it is believed that the structure of the magainins — in particular a long, repeating helix — is important to their bactericidal activities. Gellman's team created their beta-peptide to mimic this structure. "We built the same shape out of unnatural blocks, and got the same results," said Gellman.

In an amino acid, the alpha carbon is the one closest to the carboxyl group (COO-.) The beta carbon is the next one in the chain. A beta-amino acid is formed when the amino group (NH3+) attaches to the beta carbon instead of to the alpha carbon. In Beta Tyrosine, the amino group is attached one carbon closer to the aromatic ring than in the natural form.

The beta-amino acids that Gellman uses differ only slightly from natural amino acids. All amino acids have a central carbon atom, called the alpha carbon. Most have a side chain that begins with another carbon atom, which organic chemists label the beta carbon. A beta-amino acid is formed when the amino group (NH3+) attaches to the beta carbon instead of to the alpha carbon. For example, in the beta version of one amino acid, tyrosine (see illustration), the amino group is attached one carbon closer to the aromatic ring than in the natural — or alpha — form.

By using beta-amino acids to build his peptide, Gellman hopes to avoid some of the problems associated with using natural magainins as drugs, such as their propensity to be chewed up by the body's digestive enzymes. The synthetic amino acids that make up the beta-peptide are not recognized by these enzymes, making the peptide a strong candidate for use as an internal medication.

It may be possible to use some magainins topically, effectively avoiding destruction by digestive enzymes. For example, one type of magainin called pexiganan has been shown to kill more than 3,000 different strains of bacteria. A topical antibiotic for treating diabetic skin ulcers containing pexiganan as the active ingredient is under evaluation by the Food and Drug Administration.

Gellman's molecule may confer another advantage as well. Bacteria may have more trouble developing resistance to the unnatural proteins. In addition, the structure of the magainin that the beta-peptide mimics has been selected through evolutionary pressure. Bacteria have had millions of years to evolve a defense, yet apparently have not. "If the bacteria have not developed a defense by now, perhaps they won't anytime soon," said Gellman.

While the synthetic beta-peptide looks promising, Gellman cautions that it needs to be tested in animals, and eventually humans, before it can be commercially marketed as an antibiotic.

But before large-scale testing can even begin, a better method of synthesis needs to be developed. Gellman acknowledges that synthesizing the peptide takes a lot of work. He anticipates that other chemists, more skilled in synthesis techniques than he, will participate in the search for a more efficient process. "If we demonstrate this is useful, somebody else will optimize the synthesis," said Gellman.

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