Deathcap Mushroom (Amanita) has been a “regicide” for centuries, but may be losing its primacy.Scientists have discovered a possible antidote to a deadly mushroom toxin.
Deathcaps, which grow up to 15 centimeters in height and have discreet tawny or yellow-green tops, taste very delicious, according to those who survived the accidental eating. But then the toxin can cause vomiting, seizures, severe liver damage, and death. Roman Emperor Claudius is believed to have died from consuming this mushroom in 54 AD, as did Holy Roman Emperor Charles VI in 1740. Hundreds of people now die each year from eating poisonous mushrooms, with the death toll capped at his 90. % of fatalities.
Despite their lethal reputation, the death cap continues to have scientists speculating on how they kill. But when researchers recently identified a potential antidote, they also focused on the human biochemical pathway required for a mushroom toxin (called alpha-amanitin) to enter cells. The antidote, a chemical named indocyanine green, blocks that pathway. The team reported these findings as follows: Nature Communications May 16th.
“That’s great,” says Helge Bord, a natural products chemist at the Max Planck Institute for Terrestrial Microbiology in Marburg, Germany. “Alpha-amanitin is actually one of the most dangerous compounds in nature.”
A “very modern” approach
Despite Deathcap’s long history of poisoning people, doctors have little to offer people who accidentally ingest Deathcap other than supportive care. The region seemed ripe for research, so Qiaoping Wang and Guohui Wang, drug development researchers at Sun Yat-sen University in Guangzhou, China, decided to dive in.
Scientists have found an antidote to jellyfish poison using a method Wang and colleagues developed years ago. They first used CRISPR-Cas9 gene-editing technology to create pools of human cells, each with mutations in different genes. We next tested which mutations help cells survive exposure to α-amanitin.
This ‘CRISPR-Cas9 screen’ revealed that cells lacking a functional version of an enzyme called STT3B were able to survive on α-amanitin. STT3B is part of a biochemical pathway that adds sugar molecules to proteins. Blocking this pathway somehow blocks alpha-amanitin from entering the cell and prevents the toxin from completely destroying it. No one thought that STT3B was involved in α-amanitin toxicity. “We are absolutely amazed by this finding,” Wang said.. The researchers will continue to investigate how pathways involving STT3B normally introduce α-amanitin into cells.
The second step in the researchers’ strategy involved sifting through approximately 3,200 compounds looking for compounds that block the action of STT3B. Among these compounds they discovered indocyanine green. Indocyanine green is a dye developed by the photography company Kodak in the 1950s and has since been used in medical imaging, for example to visualize blood vessels in the eye and blood flow in the liver. Only about 50% of mice treated with indocyanine green died from alpha-amanitin poisoning, compared with 90% of mice not treated.
Toxicologist Jzy Patoczka of the University of South Bohemia in České Budějovice, Czech Republic, says researchers are excited about this method of finding antidotes, calling it “very modern.” Bode believes that similar experiments could identify antidotes for the bacterial toxins that cause sepsis, which is currently difficult to treat.
Transfer to clinic
The US Food and Drug Administration and the European Medicines Agency have already approved indocyanine green for use in imaging. The chemical is known to be safe in certain doses, so Wang and Wang hope to start human trials soon, but funding may be difficult to find and trials would have to rely on someone who accidentally ingested Deathcap. Timing is key in these studies, said Felix Carvalho, a toxicologist at the University of Porto in Portugal. The researchers began treatment with indocyanine green four hours after administering alpha-amanitin to the mice, but most of those who ate deathcap were found to be severely ill. Do not visit the hospital for 24-48 hours after “By then it might be too late,” says Carvalho.
Still, researchers are excited about the medical advances this method could bring. “There should be more scientific studies like this,” says Patochka.
This article is reprinted with permission and was first published on May 16, 2023.
