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Scientists at the Donald Danforth Plant Science Center have discovered a microbe that can improve the processing of life-saving opiate treatments, according to a study recently published in Nature Sustainability.

One of out every 65 deaths in Missouri in 2017 were due to opioid overdoses, according to the Missouri Department of Health and Senior Services. One critical way to combat this crisis is to increase access to overdose and addiction treatment drugs, such as naloxone and buprenorphine.

“We’ve gotten over 20,000 doses of naloxone out there over the past three years,” said Brandon Costerison, Project Manager for the MO-HOPE project, an initiative that seeks to reduce opioid overdose deaths in Missouri. “But we could always use more.”

As the demand for opiate treatment drugs continues to rise, questions about how to sustainably manufacture them become more pressing. The current process for producing opiate treatments is expensive, energy intensive, and requires the use of hazardous chemicals that can cause respiratory problems for workers. These challenges have led scientists around the world to pursue alternative methods for opiate treatment production.

Now, after decades of searching, researchers at the Donald Danforth Plant Science Center, a not-for-profit research institute based in Creve Coeur, have identified a potential avenue forward.

The search began 20 years ago when Toni Kutchan, vice president for research and Oliver M. Langenberg distinguished investigator at the center, and last author of the study, looked for a solution in sludge from opium poppy processing.

“We kind of go with the assumption that anything that you’re looking for, if you look to nature, you can find it,” Kutchan said.

The process of extracting opiate compounds from plants is not entirely efficient, so some compounds get released into the waste stream. Organisms, particularly microbes, that live in the waste get exposed to these compounds and can evolve to break them down.

“Microbes can do just amazing amounts of chemistry,” Kutchan said. “It’s just a question of finding which microbe and how it’s doing that degradation.”

In this case, Kutchan and Megan Augustin, research associate at the plant center and first author of the study, were looking for a microbe that could breakdown thebaine, a compound required for the production of opiate overdose and addiction treatments, including naloxone, naltrexone and buprenorphine.

They started their research by isolating individual microbes from the sludge sample. The sludge likely contained hundreds of thousands, if not millions, of microorganisms, but eventually they narrowed down the pool to a single bacterial species that was capable of degrading thebaine.

The next step was figuring out how the bacteria was able to perform this degradation. Augustin and Kutchan thought the bacteria contained an enzyme (a molecule that speeds up the rate of chemical reactions) that could degrade thebaine. To identify the potential enzyme, they grew the bacteria in media containing thebaine and media without it to isolate genes expressed only when thebaine was present. After an extensive curation process and many rounds of experimentation, they identified one gene that encoded a single enzyme that could break down thebaine.

“First I cried … happy, happy tears … then I celebrated,” Augustin said. “There’s this feeling that you get when you discover something because you know, in that moment, you are the only person in the entire world that knows this thing.”

“But then you worry that you got it right,” Kutchan said. “You go back and do more experiments and more controls just to be really sure.” They tested their newly discovered enzyme 50 to 100 times to confirm its activity across various conditions, including those frequently used in industry.

Although previous studies have identified enzymes capable of degrading thebaine, none could easily be applied to a commercial setting for opiate treatment production until now.

“It turned out to be … a really robust, simple enzyme that would be amenable to a commercial process in an industrial setting,” said Kutchan, “that was the second time of getting really excited.”

The next challenge will be scaling up production of the enzyme for commercial use. Augustin and Kutchan estimate they need 10 to 100 times the current amount to meet industrial scale and are currently looking for partners to help with this process.

There is precedent for increasing enzyme production in industry, which gives them hope. “We think it’s quite possible with the right input and the right experiments,” Augustin said.

While the enzyme is highly effective at processing opiates, it can also break down numerous other compounds, such as those used to treat Alzheimer’s disease and motion sickness. “This report is very interesting and promising for (the) chemical industry to produce more divergent chemicals, especially pharmaceuticals,” said Fumihiko Sato, professor emeritus in the Graduate School of Biostudies at Kyoto University in Japan, who was not involved with the study.

“It’s an exciting discovery,” said Neil Bruce, professor of biotechnology at the University of York in England, who was not involved with the study. “For a long time, (researchers) have been looking for enzymes that can perform this reaction … this one looks like a good candidate … that gives root to a cleaner process.”

If enzyme production can effectively be scaled up for industry, then this discovery has the potential to reshape how opiate treatments, as well as numerous other drugs, are manufactured. By reducing chemical waste, health hazards and energy use, microbes can make drug production cleaner and more sustainable.

“For me, the most important thing is that we, as a society, focus on sustainability and using biocatalysts to do a lot of the chemistry that is traditionally done with chemicals is a great way forward,” Augustin said.

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