A new way to block the action of botulinum toxin has been found by investigators in Australia, which may help develop effective treatments of the life-threatening disease botulism. The study is published online (August) in the International Journal of Biological Chemistry.
A new way of blocking the update of the toxin using a new class of drug called dynamin inhibitors has been discovered by a team made up of investigators from the Queensland Brain Institute (QBI), and the University of Newcastle and the Children's Medical Research Institute.
QBI Associate Professor Fred Meunier, who led the investigation said,
"We have designed and tested a new molecule called Dyngo-4a™ which prevents botulinum toxin from entering nerve cells. Dyngo-4a™ works by blocking the action of a protein called dynamin which plays a key role in controlling how most molecules can enter nerve cells."
Botulism is a rare condition that involves progressive weakness and can be fatal. Botulism is caused by botulinum toxin, which is made up by the clostridium botulinum bacterium found naturally in soil, sediments, raw foods (including seafood) and honey.
For countries, such as the United States, development of more effective treatments is a high priority due to terrorists attempting to use botulium toxin as a bioweapon.
Associate Professor Meunier explains, "The toxin that causes botulism is one of the most deadly agents known - it's been estimated that a single gram of it in crystalline form could kill more than one million people if distributed evenly." Antibodies that bind some of the toxin before it reaches nerve cells is, at present, the only known treatment for botulism.
Meunier adds, Dyngo-4a™ drastically delayed the onset of paralysis, botulism's most lethal symptom, by over 30%. "This is significant because it may provide extra time for antibodies to take effect and minimize symptoms. Our research is the first to identify the protein dynamin as a suitable drug target for preventing botulinum toxin entering nerve cells throughout the body." said Meunier.
Like anthrax, botulinum toxin is a biological agent of international concern due to its potential of being used as a lethal weapon and a serious threat to public health.
Although rare, in 5-10% of cases botulism infections can be fatal, The World Health Organization highlights, and every year several hundred children die from it.
Professor Robinson explains,
"Current treatment options for botulism are expensive and not readily available to the public. Therefore any new developments that could lead to improved treatment options and be more widely accessible, particularly in large scale bioterrorism situations, are very welcome."
The Medicinal Chemistry team of Professor Adam McCluskey at the University of Newcastle designed Dyngo-4a™.
The investigation may also have wider implications, with the new discoveries potentially being useful to develop these compounds further for a range of other serious infections.
At present, Dyngo-4a™ and other dynamin inhibitors are undergoing primary stage laboratory testing for their suitability as possible treatments for a range of diseases.
"Our discovery not only opens up the possibility of better treatments for botulism, it also provides a new starting point for investigating potential treatments for other infectious diseases which use the same pathway to enter nerve cells in the body,"
Professor Robinson explains. Testing the effectiveness of higher doses and establishing the window of opportunity for treatment following exposure to botulinum toxin, will be the next steps for the investigators.
Written by Grace Rattue