'As a group, defensins exhibit activity against many types of bacteria, fungi, protozoa and even viruses. It is entirely possible that fungal defensins will be discovered that could be developed against all of these human pathogens.'

A international team -- including scientists from Denmark-based biotech company Novozymes, Georgetown University Medical Center and the David Geffen School of Medicine at UCLA -- collaborated on the study.

The researchers isolated plectasin -- the first defensin ever found in fungi. Defensins are peptides, miniature protein molecules produced by many animals, including humans, to protect themselves from infection. However, plectasin targets certain bacteria more specifically and is believed to be more potent.

Opens a Vast Universe

When tested in the laboratory and in animals, plectasin proved to be highly effective against several common bacteria, including strains that are now resistant to conventional antibiotics. These bacteria are responsible for such diseases as meningitis, community-acquired pneumonia, strep throat, life-threatening sepsis, and flesh-destroying skin infections.

The discovery of plectasin has implications for the development of defensins as a treatment against many common deadly infections, and may initiate a new era of antibiotic discovery and development, says study co-author Michael Zasloff, MD, PhD, Professor in the Departments of Surgery and Pediatrics at Georgetown University Medical Center.

The field of antibiotic development has not changed much since 1929, Zasloff says, when Alexander Fleming realized that the fungal bread mold Penicillium -- which had landed by chance in a Petri dish -- produced a substance that eliminated colonies of staphylococcal bacteria.

"Most antibiotics used by humans are produced by fungi and certain soil bacteria," Zasloff notes.

"Using our existing tools of discovery, we have failed to uncover any new classes of antibiotics from these sources over the past decade. However, by utilizing a new genetic approach that allowed the team to discover plectasin, we now know that a whole class of antibiotics has been overlooked," he adds.

"This finding -- and the existence of about 200,000 additional species of fungi -- opens up a vast universe to explore for novel peptide antibiotics," says co-author Robert Lehrer, MD, Distinguished Professor of Medicine at the David Geffen School of Medicine at UCLA. If proven safe and effective in humans, plectasin could be on the market by 2012, he predicts.

Latest Genetic Science

All life forms have to defend themselves against microbial invaders -- bacteria, fungi, viruses -- and to do this, they produce antimicrobial defensin peptides. In humans, defensins are made by specific white blood cells and immune cells that later engulf foreign invaders, and by the skin and mucous membranes, in order to kill microbes before they invade protective barriers.

Fungi likely have a similar system of defense, especially since these plant-like organisms live off rotting matter, says Zasloff.

"They must compete with other organisms, like bacteria and viruses, which also want to consume the same meal. In addition, they need to defend themselves from being eaten by the microbes which surround them," he explains.

But no one had been able to find defensins in fungi using traditional research techniques, which involved growing fungi in liquid cultures and then testing the culture to see if it contained any antibiotic molecule.

For this study, the research team employed the latest genetic science to search for the defensins they thought fungi must have. Selecting the Pseudoplectania nigrella species of fungus may have been serendipitous, but the Novozymes team used state-of-the-art biotechnology to intercept and interpret its genetic messages and exhibited tremendous skill in producing plectasin efficiently, economically, and in large amounts, according to Lehrer.

"I started working on antimicrobial peptides over three decades ago," he remarks, "and my laboratory first described human defensins in 1985. So, the discovery of plectasin makes me feel like a grandfather."

Very Different from Traditional Antibiotics?

Plectasin resembles defensins found in spiders, scorpions, dragonflies and mussels -- thus suggesting that the defensins found in insects, molluscs and fungi arose from a common ancestral gene, the researchers say. Based on this information, the scientists now believe that defensins appeared in living things more than a billion years ago.

In laboratory tests, plectasin showed potent activity against several species of Gram-positive bacteria, and was especially active against S. pneumoniae (the leading cause of pneumonia), including all known clinical strains and those that are now resistant to conventional antibiotics.

"That is important because increasing bacterial resistance to conventional antibiotics threatens the future of many antibiotics in current use," Zasloff points out.

In mouse studies, plectasin showed extremely low toxicity, and was as effective as vancomycin and penicillin in curing the animals of experimental peritonitis (inflammation of the lining of the abdominal cavity, which can be deadly), as well as pneumonia caused by S. pneumoniae, the researchers report.

"Although the precise mechanism by which plectasin exerts its antimicrobial activity is still under investigation, it may work by a mechanism that is very different from traditional antibiotics," Zasloff says.

"As a group, defensins exhibit activity against many types of bacteria, fungi, protozoa and even viruses. It is entirely possible that fungal defensins will be discovered that could be developed against all of these human pathogens," Zasloff adds.