Researchers Strike Genetic Gold in Search for Natural Products
There’s a goldmine at the University of Illinois. But in this case, the nuggets being uncovered are genes that can produce new natural compounds for pharmaceuticals and other human uses. It’s all part of a collaborative effort among five labs known as Mining Microbial Genomes for Novel Natural Products.
In 2007, the U of I team struck gold by discovering an enzyme that can perform an unprecedented chemical reaction. This year, they announced the mechanism behind that unique chemical reaction, a discovery that could boost production of an important weed killer and even help uncover natural compounds to develop new antibiotics.
The key behind the effort, taking place at the Institute for Genomic Biology, is to look for specific genes, rather than the natural compounds themselves, says Wilfred van der Donk, a chemistry professor who runs one of the program’s five labs.
“The 1960s and 1970s were the heyday for discovering natural compounds for all types of uses, including antibiotics,” he says. “But it was like picking low-hanging fruit.” Natural products were abundant and easy to find.
As the years passed, it has become more difficult to keep up the same discovery rate. According to van der Donk, an estimated 99 percent of the natural compounds being found turn out to be compounds already discovered.
One solution, he says, is to search for genes rather than compounds.
Bacteria can produce natural products for many human uses, such as controlling weeds or fighting other bacteria. Therefore, researchers are exploring the genomes of bacteria, looking for the genetic triggers behind natural products. He says it has been “eye-opening.”
In the past, researchers believed that certain types of bacteria typically create two or three natural compounds for human use. With this new approach researchers are finding that bacteria can actually produce closer to 20 or 25 natural products.
The U of I team has been moving on many fronts, including a probe of phosphinothricin (PT), a bacterial compound used in top-selling herbicides. While studying PT, they discovered an enzyme that could break carbon-carbon bonds without requiring anything except oxygen.
Now they believe they have pinpointed the mechanism behind this unique chemical reaction, which may boost the production of PT. This knowledge may also help in the discovery of other important natural products.
By developing new ways to discover natural products, the U of I team hopes to give new life to the antibiotic discovery effort. It costs about $1 billion to develop a new drug; to recoup these costs, companies are focusing on more profitable drugs that people with chronic diseases take all their lives, rather than antibiotics, which might be taken for infections for only two weeks. Also, the high rediscovery rate in hunting for new antibiotics drives companies away.
“We know we have this problem of antibiotic resistance in bacteria, but very little is being done to head off the coming problem,” van der Donk says. “It’s like we’re on a train heading for a tunnel that has caved in.”