Researchers have identified a compound that strongly inhibits the botulinum neurotoxin, the most toxic compound known. Such an inhibitor compound, nitrophenyl psoralen (NPP), could be used as a treatment to reduce paralysis induced by botulism. Botulinum neurotoxin is considered a potential biological weapon because there is no FDA-approved antidote. The research is published in Applied and Environmental Microbiology, a journal of the American Society for Microbiology.
In the study, the researchers' first step was to identify the enzyme within the botulinum neurotoxin that damages the neurons, causing paralysis. They then examined a library containing more than 300 natural compounds from Indian medicinal plant extracts, looking for enzymes that could neutralize the damaging activity of neurons.
"Using high throughput screening, we identified one of the compounds, nitrophenyl psoralen, as having particularly strong activity against the enzyme that damages neurons," said corresponding author Bal Ram Singh, PhD, Professor and Director of the Center for Botulinum Research Institute of Advanced Sciences. , Dartmouth, MA.
The researchers then tested NPP activity in vitro and in cell culture against botulinum neurotoxin type A, which is the most potent serotype among the seven botulinum toxin serotypes. NPP type A showed potent anti-botulinum toxin activity, with low toxicity to human cells. (image: botulinum neurotoxin molecular model)
"NPP also showed activity to reverse the rat muscle paralysis induced by botulinum neurotoxin type A," said Dr. Singh.
Although fewer than 200 cases of botulism occur worldwide each year, they "cost more to treat than the millions of outbreaks of salmonella that occur, making botulism the most expensive form of food poisoning," said Singh. Botulinum toxin is produced by Clostridium botulinum, a soil bacterium that is ubiquitous and difficult to kill. Spores can survive being boiled.
Botulism can be acquired through other ways than food poisoning, such as wound contamination and colonization of the digestive tract of children and infants.
Drugs derived from Psoralen are already approved by the FDA in the United States. This would likely accelerate the drug approval process for NPP, Dr. Singh said.
The research originated from the work of Dr. Singh's group on the biochemical basis of Ayurveda, a herbal system widely used in India. Natural products, such as those used in Ayurveda, have more diverse structures, less toxicity and better drug-like properties than synthetic ones. As founding director of the Center for Indigenous Studies at UMass Dartmouth, he considered natural herbal compounds as a source of countermeasures against botulism. This led to discussions and then to a collaboration in this work with Professor Virinder Parmar, head of the Department of Chemistry at the University of Delhi.
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