Experimenting with drugs for science's sake

September 15, 2000

Geoff Watts explains a quest to find bacteria with a taste for heroin.

Humans have been giving thanks for opium for at least 3,000 years. Now, our oldest painkiller has attracted the attention of our newest technology: gene manipulation. Most of today's opiate drugs are semi-synthetic: chemical derivatives of morphine, the main natural component of opium. Juggling with the basic molecule can radically alter its potency and actions - which include suppression of the cough reflex as well as analgesia. Morphine derivatives also make narcotic antagonists for use in treating drug addiction or overdose. But of the hundreds of morphine variants made over the past 40 years, only about 20 are in common clinical use. Some of the chemical conversions required are difficult and expensive. Morphine is a complex molecule, incorporating many "functional groups", which must be altered when making derivatives.

"The problem with carrying out chemical changes to a molecule like this is that functional groups may be very reactive," says Neil Bruce of the Cambridge University Institute of Biotechnology. "You have to protect them while you're modifying other groups. To do this, you attach blocking agents. When you've made the changes, you remove the blocking agents. So you have a series of steps - blocking, unblocking and so on. Consequently, you get a lower yield of the final product.

"When you want to make a compound such as hydromorphone, which is what we've been doing, you have to go through about seven steps. If you could devise a biological route that converts morphine into hydromorphone at high yield, you could make it more cost-effectively."

Bruce is trying to persuade bacteria to do the manufacturing for him. "We first got involved in this through the Customs and Excise. They wanted us to design a system for detecting heroin using a biosensor with an enzyme system for recognising the drug.

"My approach was to find bacteria that would use heroin as a food source. Not many bacteria naturally metabolise opiates. We went to poppy fields in Tasmania, and isolated the bacteria from soil samples. The thinking was that bacteria that had been exposed to these compounds would have adapted to them, either using them as food or detoxifying them."

The search was successful. But there was no single organism that would carry out the complete morphine-hydromorphone conversion. So Bruce and colleagues used a pick-and-mix approach to assemble a custom-built microbe. "We've now got a system that will produce hydromorphone with a 90 per cent yield in a two-enzyme process, using genes from two different organisms."

The industrial potential of the new microbe is being investigated by Mike McPherson of the Edinburgh drug company Macfarlan Smith Ltd. He says:

"We're reasonably encouraged, but there's a lot of work to do."

Even if the conversion that McPherson and Bruce are testing fails commercially, they will not be deterred. "While this process may or may not succeed," says Bruce, "it should be close enough to give companies the confidence to look more at biological routes for making compounds."

Details: http://www.biot.cam.ac.uk/ xncb.htm

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