Biomedicine

Natural Products Made in a Test Tube

Researchers have developed a new technique to synthesize drugs faster.

Chemists spend hours synthesizing compounds that a cell can make in minutes. Now, researchers have demonstrated a way to bridge that gap. They’ve synthesized a complex natural product by taking enzymes used by a cell and mixing them with simple starting materials in a single flask. The one-step process offers a simple, potentially quicker way to manufacture drugs based on molecules found in nature.

An antibiotic cocktail: In just a couple of hours, researchers synthesized an antibiotic by mixing enzymes and simple compounds in a laboratory flask. It was the first time that the biosynthetic pathway for a complex natural product had been mimicked outside of a cell.

Bradley Moore of the Scripps Institution of Oceanography and his colleagues at the University of Arizona synthesized enterocin, a broad-spectrum antibiotic found in the marine organism Streptomyces maritimus. “It’s probably not going to make the best drug, but it presented a very nice proof of principle,” Moore says.

The molecule’s complex structure and the chemical reactions needed to create it had not been achieved before with other techniques. The study appeared online last month in Nature Chemical Biology.

When scientists discover a useful product in a microbe or a plant, the first step is usually to isolate that compound from the original source. But in order to study it and develop it as a drug, scientists need a way to synthesize it in large amounts.

Conventional methods for synthesizing natural products are very powerful, although they can be laborious, Moore says. The process often involves many individual chemical reactions that must be done in sequence. After each reaction, the products must be purified and isolated before researchers can move on to the next step.

In the method described by Moore’s group, the bulk of the labor comes while preparing for that moment when the enzymes and starting materials are combined. “We can actually make the compound in two hours–put it in the flask, shake it, and it’s made,” Moore says. But making the enzymes required cloning genes and expressing them in microorganisms, which took months of work. “There’s an up-front cost to generating the enzymes, but it’s a one-time deal,” Moore says, because once a scientist has a supply of enzymes, he or she can simply draw from that to create a second batch of the antibiotic.

“I think it’s very nice work,” says Xi Chen, a chemist at the University of California, Davis, whose group uses enzymatic techniques to synthesize carbohydrates. For complicated compounds like enterocin, “a lot of enzymes are involved in the process, so it’s been very difficult to get individual enzymes out and put them together for making the product,” Chen says. Moore and his colleagues had worked out the biosynthetic pathway in the S. maritimus, so they knew the steps involved.

Another way to produce enterocin would be to genetically engineer a microorganism with that pathway–a familiar method in drug manufacturing. But putting that process in a flask “allows you to tinker more,” Moore says. For example, the enzymes or starting materials can easily be changed, yielding a library of different products. That flexibility makes the method a valuable tool for discovery.

Scott Snyder, a synthetic-organic chemist at Columbia University, was impressed by the enzymatic method’s ability to do a particular reaction known as a Favorskii rearrangement. “If we were to attempt this in a flask with the standard reagents you would utilize to do this, there is no way one would get the selectivity leading to enterocin as the final product,” he says. “It’s mechanistically quite complicated.”

Snyder sees synthetic methods based on enzymes ultimately complementing organic synthesis methods. “If it’s easy to alter an enzyme to create a desired analog, then an enzymatic pathway would provide a full solution,” he says. “But if that doesn’t exist, then you need someone to come in with a more traditional approach to make that compound.”

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