By Sharon Kingman

Special To BioWorld Today

LONDON -- The discovery of a novel peptide antibiotic produced by human skin is giving rise to hope that a whole new family of related antibiotics is waiting to be discovered. The German researchers who made the discovery believe that the compounds are so old in evolutionary terms that bacteria would not be able to mutate in order to become resistant to them.

Jens-Michael Schroder, of the department of dermatology at the University of Kiel, in Germany, told BioWorld Today: "It seems likely that in principle there is a whole battery of antibiotics produced by human skin, with different ones being produced in different parts of the body." This could explain how the microbial flora of the mouth, for example, is maintained in a different way than that of the urogenital tract, he said.

Schroder and his colleagues report their finding in the June 26 Nature in a letter titled "A peptide antibiotic from human skin." Commenting on the paper, Michael Zasloff, executive vice president of Magainin Pharmaceuticals Inc., of Plymouth Meeting, Pa., said, "The discovery of this new compound begins to explain features of human health that, to date, have been hard to understand. It provides potential answers to questions such as why skin is normally healthy; why, when humans bite their tongue, the wound doesn't become infected; and why the cornea of the eye remains healthy even though all kinds of things blow into it."

Zasloff said it would be possible to produce new drugs based on the natural antibiotic, if a way could be found to manufacture them cheaply. He also predicted that new immunostimulants would soon be developed which could be applied to skin, lungs or gut, for example, and which would intensify the production of the natural antibiotics present in these tissues.

The starting point for Schroder and his colleagues was the observation that patients with the skin disease psoriasis suffer fewer skin infections than would be expected. So the team decided to find out whether antimicrobial peptides were present in psoriatic skin lesions.

They first bound whole killed bacteria to the matrix of an affinity column and then passed extracts from the skin samples along this column. This allowed them to purify bound peptides. Eventually, after additional purification, they were able to recover up to 400 micrograms of a pure antimicrobial peptide from a 50 gram sample of psoriatic scales.

Analysis of the amino acid sequence of this peptide showed that it was homologous to an antimicrobial peptide found on the tongue and in the trachea of cows, which is produced in response to microorganisms and inflammatory cytokines. In addition, the peptide had about 30 percent homology with a molecule described by Zasloff and colleagues earlier this year, which they had called human beta-defensin (hBD-1). (See BioWorld Today, Feb. 21, 1997, p. 1.) Schroder's group therefore called their newfound peptide hBD-2.

hBD-1 is expressed abundantly at sites including the respiratory tract, urogenital tract, kidney and salivary glands. Tests carried out by Schroder and colleagues showed that hBD-2, by contrast, is expressed at high levels in skin, lung and trachea, but at lower levels in kidney, uterus and salivary gland tissue. They also found that hBD-2 is very good at killing gram-negative bacteria, such as Escherichia coli and Pseudomonas aeruginosa, as well as the yeast Candida albicans, but less efficient at killing Staphylococcus aureus, which is gram-positive.

Furthermore, production of hBD-2 -- unlike hBD-1 --can be upregulated by the presence of bacteria or inflammatory cytokines such as tumor necrosis factor alpha.

"The remarkable feature of hBD-2 is that it is profoundly inducible," Zasloff said. "The system responds directly to bacteria, as well as to mediators that are produced by other cells when they are exposed to bacteria. It is this feature which positions this molecule as a truly defensive entity."

He called for more detailed studies into the role of the defensin system in the maintenance of health. "It is also possible that human diseases in which there is chronic inflammation, such as psoriasis and inflammatory bowel disease, could represent a failure of this defensive system," Zasloff said.

Schroder added that people who are susceptible to recurrent urinary infections or chronic skin infections, for example, may have defensins which are slightly defective and so do not kill bacteria effectively. "We know that these peptides work by producing pores in bacterial cell walls, but perhaps when the structure of the defensin is changed pore formation is less than optimal," he said.

Zasloff and his colleagues showed in their paper, in Cell in February, that fluid from normal epithelial cells in the lungs can kill both P. aeruginosa and S. aureus, whereas the airway secretions from patients with cystic fibrosis cannot. The Magainin team also demonstrated that if they dilute the salt content of the airway secretions from the cystic fibrosis patients down to normal levels, the antibiotic activity present in the secretions returns and the bacteria die.

"We feel that hBD-2 is a long sought-after molecule which appears to be Nature's way of protecting us against P. aeruginosa and which, like hBD-1, fails in cystic fibrosis," Schroder concluded. *