NEW YORK, Feb. 15, 1999 -- Scientists at New York University School of Medicine and The Rockefeller University have discovered the structure of a key compound that enables a dangerous bug to cause devastating infections. They have also designed molecules that block the compound's effects, opening a novel way to combat these infections.
The scientists, led by NYU's Richard Novick, M.D., and Rockefeller's Tom Muir, Ph.D., found that an unusual peptide compound activates the disease-causing mechanism of Staphylococcus aureus, a notorious bacterium that each year infects some 500,000 hospitalized patients. By substituting parts of the compound with different chemicals, the researchers created compounds that dramatically weakened Staph infections in mice, according to a joint study published in the Feb. 16 issue of the Proceedings of the National Academy of Sciences.
"One of our long-term goals is to develop novel therapies to combat Staph," says Dr. Novick, Professor of Microbiology and Medicine at NYU School of Medicine. "Our study is extremely significant in that regard because it demonstrates the feasibility of constructing synthetic analogues that turn off Staph's ability to cause infection while leaving the bacterium intact. This may provide a way to get around the problem of antibiotic resistance because our analogues don't kill bacteria," he says.
Staphylococcus aureus causes a wide range of illnesses, from relatively minor skin abscesses to life-threatening toxic shock syndrome and other illnesses. Antibiotics kill the bacterium, but in recent years the wily bug increasingly has become resistant to the most commonly used antibiotics. The development of antibiotic-resistant strains of Staph and other bacteria has caused widespread alarm that one day there may be many so-called superbugs resistant to all known antibiotics.
Several years ago, Dr. Novick's laboratory discovered that a master gene, or global regulator, regulates a signaling pathway in the bacterium that ultimately results in its release of virulent toxins. It is these toxins, rather than the bug itself, that cause illness; indeed, strains of Staph regularly inhabit our nasal passages without causing disease.
In a study published two years ago in the journal Science, Dr. Novick and co-workers reported that a peptide, a small piece of protein, secreted by Staph activates the global regulator, and that each strain of Staph tested produced a specific peptide. Moreover, the peptide produced by one strain inhibited the global regulator of a second strain, meaning that the first strain could potential block the ability of the second strain to cause inhibition.
In the new study, Drs. Novick and Muir describe the chemical structure of these peptides and custom design molecules that can inhibit their activity in mice, providing a novel way to disarm Staph rather than killing it outright. The ring-shaped regulatory peptide is composed of seven to nine amino acids, the building blocks of peptides, and an unusual sulfur-containing bridge called a thiol ester. The inhibitor compounds were designed by replacing the thiol-ester bridge with other compounds, but retaining the peptides' ring structure.
In the study, the researchers also were able to dramatically weaken Staph infections in mice who had large abscesses on their backs caused by the bacteria. The abscesses became dramatically smaller in animals treated with specific inhibitory peptides compared to those in untreated animals, indicating that the inhibitor had weakened the bacterial infection.
Journal
Proceedings of the National Academy of Sciences