New Class Of Antibiotics Effective Against Drug-resistant Bacteria Discovered In Fungi

Reporting in the October 13 issue of Nature, a team fromDenmark-based biotech company Novozymes, and researchers fromGeorgetown University Medical Center and the David Geffen School ofMedicine at UCLA, say they have isolated "plectasin," the firstdefensin ever found in fungi. The research was performed at Novozymeslaboratories in Denmark.

Defensins are peptides, miniature protein molecules that areproduced by a wide range of animals to protect themselves againstinfection. Humans have defensins in their white blood cells and intheir skin, for example, but it is believed that this new fungaldefensin, plectasin, is more potent and targets certain bacteria morespecifically.

Indeed, when plectasin was tested in the laboratory and inanimals, it proved to be highly effective against the bacteriaStreptococcus pneumoniae, and Streptococcus pyogenes, including strainsthat are now resistant to conventional antibiotics. These bacteria areresponsible for such diseases as meningitis, community-acquiredpneumonia, strep throat, life-threatening sepsis, and flesh destroyingskin infections.

The discovery of plectasin has implications for the developmentof defensins as a treatment against many common, and deadly,infections, and may initiate a new era of antibiotic discovery anddevelopment, said study co-author Michael Zasloff, M.D., Ph.D.,Professor in the Departments of Surgery and Pediatrics at GeorgetownUniversity Medical Center.

Zasloff says that the field of antibiotic development has notchanged much since 1929 when Alexander Fleming realized that the fungal"bread mold" Penicillium, which had landed by chance in a Petri dishproduced a substance that eliminated colonies of staphylococcalbacteria.

"Most antibiotics used by humans are produced by fungi and certain soilbacteria," he said. "Using our existing tools of discovery, we havefailed to uncover any new classes of antibiotics from these sourcesover the past decade. However, by utilizing a new genetic approach thatallowed the team to discover plectasin, we now know that a whole classof antibiotics has been overlooked."

"This finding (plectasin), and the existence of about 200,000additional species of fungi, opens up a vast universe to explore fornovel peptide antibiotics," said co-author Robert Lehrer, M.D.,Distinguished Professor of Medicine at the David Geffen School ofMedicine at UCLA. Plectasin, if proven safe and effective in humans,could be on the market by 2012, said Lehrer.

Zasloff and Lehrer are known internationally as experts inantimicrobial peptides - the class of antibiotics that plectasin fallswithin - and in this study they collaborated with Novozymes, a Danishbiotech company that led the research. Zasloff and Lehrer are the onlytwo scientists from U.S. universities on the team of 20 researchers whoco-authored the research paper.

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

Researchers believe that fungi have a similar system of defense,especially since these plant-like organisms live off rotting matter,said Zasloff. "They must compete with other organisms, like bacteriaand viruses, which also want to consume the same meal. In addition,they need to defend themselves from being eaten by the microbes whichsurround them."

But he said no one had been able to find defensins in fungiusing traditional research techniques, which involved growing fungi inliquid cultures and then testing the culture to see if it contained anyantibiotic molecule.

The research team instead used the latest genetic science to search forthe defensins they thought fungi must have. Selecting thePseudoplectania nigrella species of fungus may have been serendipitous,Lehrer said, but the Novozymes team used state-of-the-art biotechnologyto intercept ,and interpret its genetic messages and exhibitedtremendous skill in producing plectasin efficiently, economically, andin large amounts." "I started working on antimicrobial peptides overthree decades ago, said Lehrer, and my laboratory first described humandefensins in 1985. So, the discovery of plectasin makes me feel like agrandfather."

Further examination revealed that this defensin, plectasin, resemblesdefensins found in spiders, scorpions, dragonflies and mussels - thussuggesting that the defensins found in insects, molluscs and fungiarose from a common ancestral gene, the researchers say. Based on thisinformation, the scientists now believe that defensins appeared inliving things more than a billion years ago.

The investigators then turned to the National Center for Antimicrobialsand Infection Control, the Danish equivalent of the U.S. Centers forDisease Control, to test plectasin in the laboratory for antimicrobialactivity against a broad spectrum of bacteria. It showed potentactivity against several species of Gram-positive bacteria, and wasespecially active against S. pneumoniae (the leading cause ofpneumonia), including all known clinical strains and those that are nowresistant to conventional antibiotics. "That is important becauseincreasing bacterial resistance to conventional antibiotics threatensthe future of many antibiotics in current use," Zasloff said.

"In mouse studies, plectasin showed extremely low toxicity, and was aseffective as vancomycin and penicillin in curing the animals ofexperimental peritonitis (inflammation of the lining of the abdominalcavity, which can be deadly) and pneumonia caused by S. pneumoniae, theresearchers report.

"Although the precise mechanism by which plectasin exerts itsantimicrobial activity is still under investigation, it may work by amechanism that is very different from traditional antibiotics, Zasloffsaid.

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

"The research was carried out and funded by Novozymes, with Zasloff andLehrer serving as consultants to the company. Other authors of thepaper include Per H Mygind, PhD, Rikke L Fischer, PhD, Kirk Schnorr,PhD, Mogens T Hansen, MSc, Carsten P Sönksen, PhD, Svend Ludvigsen,PhD, Dorotea Raventós, PhD, Steen Buskov, PhD, Bjarke Christensen, PhD,Leonardo De Maria, PhD, Olivier Taboureau, PhD, Debbie Yaver, PhD,Signe G Elvig-Jørgensen, MSc, Marianne V Sørensen, PhD, Bjørn EChristensen, PhD, Søren Kjærulff, PhD, Niels Frimodt-Moller, MD, RobertI Lehrer, MD, Michael Zasloff, MD, PhD, and Hans-Henrik Kristensen, PhD.