Mushroom Yields First Of New Class Of Antibiotics
http://www.medpagetoday.com/Pulmonary/Pneumonia/tb/1928
Mushroom Yields First Of New Class Of Antibiotics
By Michael Smith, MedPage Today Staff Writer
Reviewed by Rubeen K. Israni, M.D., Fellow, Renal-Electrolyte and Hypertension Division, University of Pennsylvania School of Medicine
October 13, 2005
MedPage Today Action Points
* Note that this study suggests a new class of antibiotics is possible, but caution patients that more study is needed before they will be available for therapy.
Review
WASHINGTON, Oct. 13 - A small black mushroom found in the woods of northern Europe contains the first of what may be a powerful new class of antibiotics and antivirals, a researcher here says.
"I think we are looking at a whole new world of antibiotics," said Michael Zasloff, M.D., Ph.D., of Georgetown University Medical Center.
Plectasin, a peptide derived from a fungus called Pseudoplectania nigrella, is as effective as penicillin and vancomycin in combating experimental peritonitis and pneumonia in mice, Dr. Zasloff and colleagues reported in the Oct. 13 issue of Nature.
The peptide is one of a class of molecules called defensins, which have previously been found in plants and animals. Plectasin is the first to be isolated from a fungus, Dr. Zasloff said.
Plectasin was tested against a range of bacteria, including streptococcus, enterococcus, and staphylococcus, Dr. Zasloff said, but other defensins have been shown to have activity against viruses.
Since about 200,000 other species of fungus exist, he said, it seems likely that many more fungal defensins will be found, possibly allowing for highly-targeted antimicrobial drugs that will render today's broad-spectrum drugs obsolete.
"I think we as physicians are going to see assembly of a large number of antimicrobial peptides targeted against specific organisms, including viruses," Dr. Zasloff said.
The compound was isolated by scientists at the Danish biotechnology company Novozymes, which is able to produce recombinant plectasin at a commercially viable yield, price, and purity, Dr. Zasloff said.
Defensins are small cysteine-rich peptides whose function, he said, "is to allow us to live among microbes." Plectasin has very little structural similarity to defensins found in vertebrate animals or plants, he and his colleagues found, although it is similar to those found in invertebrates.
In lab assays, the compound showed potent activity against a range of Gram-positive bacteria, including several strains resistant to conventional antibiotics. It was less effective against Gram-negative microbes, the researchers noted.
In mice inoculated with a potentially lethal dose of S. pneumoniae in the peritoneum, plectasin was as effective as vancomycin, the researchers found:
* 10 mg/kg of intravenous plectasin caused the concentration of viable pneumococci in the peritoneum to fall 10-fold two hours after administration and 1,000-fold after five hours.
* 70 mg/kg of subcutaneous vancomycin produced similar decreases.
* In untreated control animals, the concentration of viable pneumococci had increased by 10 times at the end of five hours.
* Plectasin treated mice were more likely to be alive seven days after infection compared with mice in the control arm (p<.0002).
In a mouse model of pneumonia, plectasin and penicillin again had comparable efficacy, the researchers found.
The compound showed no evidence of toxicity in the mice, Dr. Zasloff said, although further study will be needed to see if it is safe to use in humans. It is very likely, however, that the efficacy seen in mice will translate to people, he said, since the bacterial targets would be the same.
Plectasin is excreted without change in the urine of mice, Dr. Zasloff said -- a sign both that it is safe to use and effective.
The discovery of the compound could not have taken place using conventional techniques, in which the fungi would be grown in liquid cultures and then tested to see if they had any antimicrobial activity.
"When this mushroom is grown in the lab, it doesn't produce much plectasin," he said.
Instead, researchers at Novozymes went "scouring through the genetic messages" of wild fungi, looking for genes that would code for secreted molecules, he said. "One of them coded for what we could clearly see was a defensin," he added.
Now, Dr. Zasloff says, a walk near his home brings dozens of mushrooms to his attention. "It's hard not to go back to the lab and see what they're making."
Primary source: Nature
Source reference:
Mygind PH et al. Plectasin is a peptide antibiotic with therapeutic potential from a saprophytic fungus. Nature. 2005; 437: 975-80.
Mushroom Yields First Of New Class Of Antibiotics
By Michael Smith, MedPage Today Staff Writer
Reviewed by Rubeen K. Israni, M.D., Fellow, Renal-Electrolyte and Hypertension Division, University of Pennsylvania School of Medicine
October 13, 2005
MedPage Today Action Points
* Note that this study suggests a new class of antibiotics is possible, but caution patients that more study is needed before they will be available for therapy.
Review
WASHINGTON, Oct. 13 - A small black mushroom found in the woods of northern Europe contains the first of what may be a powerful new class of antibiotics and antivirals, a researcher here says.
"I think we are looking at a whole new world of antibiotics," said Michael Zasloff, M.D., Ph.D., of Georgetown University Medical Center.
Plectasin, a peptide derived from a fungus called Pseudoplectania nigrella, is as effective as penicillin and vancomycin in combating experimental peritonitis and pneumonia in mice, Dr. Zasloff and colleagues reported in the Oct. 13 issue of Nature.
The peptide is one of a class of molecules called defensins, which have previously been found in plants and animals. Plectasin is the first to be isolated from a fungus, Dr. Zasloff said.
Plectasin was tested against a range of bacteria, including streptococcus, enterococcus, and staphylococcus, Dr. Zasloff said, but other defensins have been shown to have activity against viruses.
Since about 200,000 other species of fungus exist, he said, it seems likely that many more fungal defensins will be found, possibly allowing for highly-targeted antimicrobial drugs that will render today's broad-spectrum drugs obsolete.
"I think we as physicians are going to see assembly of a large number of antimicrobial peptides targeted against specific organisms, including viruses," Dr. Zasloff said.
The compound was isolated by scientists at the Danish biotechnology company Novozymes, which is able to produce recombinant plectasin at a commercially viable yield, price, and purity, Dr. Zasloff said.
Defensins are small cysteine-rich peptides whose function, he said, "is to allow us to live among microbes." Plectasin has very little structural similarity to defensins found in vertebrate animals or plants, he and his colleagues found, although it is similar to those found in invertebrates.
In lab assays, the compound showed potent activity against a range of Gram-positive bacteria, including several strains resistant to conventional antibiotics. It was less effective against Gram-negative microbes, the researchers noted.
In mice inoculated with a potentially lethal dose of S. pneumoniae in the peritoneum, plectasin was as effective as vancomycin, the researchers found:
* 10 mg/kg of intravenous plectasin caused the concentration of viable pneumococci in the peritoneum to fall 10-fold two hours after administration and 1,000-fold after five hours.
* 70 mg/kg of subcutaneous vancomycin produced similar decreases.
* In untreated control animals, the concentration of viable pneumococci had increased by 10 times at the end of five hours.
* Plectasin treated mice were more likely to be alive seven days after infection compared with mice in the control arm (p<.0002).
In a mouse model of pneumonia, plectasin and penicillin again had comparable efficacy, the researchers found.
The compound showed no evidence of toxicity in the mice, Dr. Zasloff said, although further study will be needed to see if it is safe to use in humans. It is very likely, however, that the efficacy seen in mice will translate to people, he said, since the bacterial targets would be the same.
Plectasin is excreted without change in the urine of mice, Dr. Zasloff said -- a sign both that it is safe to use and effective.
The discovery of the compound could not have taken place using conventional techniques, in which the fungi would be grown in liquid cultures and then tested to see if they had any antimicrobial activity.
"When this mushroom is grown in the lab, it doesn't produce much plectasin," he said.
Instead, researchers at Novozymes went "scouring through the genetic messages" of wild fungi, looking for genes that would code for secreted molecules, he said. "One of them coded for what we could clearly see was a defensin," he added.
Now, Dr. Zasloff says, a walk near his home brings dozens of mushrooms to his attention. "It's hard not to go back to the lab and see what they're making."
Primary source: Nature
Source reference:
Mygind PH et al. Plectasin is a peptide antibiotic with therapeutic potential from a saprophytic fungus. Nature. 2005; 437: 975-80.
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