Genome of Antibiotic Wellspring Mapped

Scientists hope it yields more potent drugs

WEDNESDAY, May 8, 2002 (HealthDayNews) -- Scientists have plotted the complete genetic map of the bacterium that is the source of most of the world's antibiotics, a feat they hope will yield more potent drugs now that existing ones are losing their effectiveness.

The germ, Streptomyces coelicolor, is a soil-dwelling bug that makes antimicrobial compounds to protect its turf.

S. coelicolor -- whose name, meaning "blue sky," refers to the hue of one of those compounds -- and similar organisms produce two-thirds of the natural antibiotics in the world's medicine chest, including tetracycline and erythromycin. They also act as natural breweries for drugs to treat cancer and suppress the immune system.

Sir David Hopwood, an emeritus researcher at the John Innes Center in Norwich, England, and his colleagues conducted the sequencing, which is reported in tomorrow's issue of Nature. A Japanese team had earlier released a partial sequence of the organism.

Knowing the germ's genome should let scientists craft entirely novel products by scrambling its genes in creative combinations, Hopwood says: "You could find new pathways of genes to mix and match and generate unnatural, natural products."

As antibiotics lose their ability to fight drug-resistant germs, the search for new agents becomes more important.

Although scientists had previously identified four gene pathways involved in antibiotic production, the sequencing effort turned up another 16 or so that make "interesting looking compounds," Hopwood says. These might be antibiotics, as well, but may have anti-tumor or other disease-fighting functions, too.

S. coelicolor (pronounced CEE-leh-color) belongs to a family of bacteria called actinomyces. These microbes are relatives of the pathogens that cause tuberculosis and leprosy.

S. coelicolor has roughly 8.7 million base pairs -- the molecular units of DNA -- and more than 7,800 genes, making it a germ of considerable heft. In fact, the single-cell S. coelicolor has more genes than yeast, which is a more structurally complex organism. Humans have about 32,000 genes, although some scientists believe the number is much greater.

Another distinguishing feature of the bug is its relatively high proportion of so-called regulatory instructions that switch other genes on and off. Hopwood's group predicts that 12 percent of the organisms' genes -- and thus the proteins they make -- have regulatory roles.

That diversity reflects its complex habitat and its status as a microbial generalist, Hopwood says. Soil contains a vast range of nutrients, such as plant and animal matter, as well as a host of threats, including chemicals, radiation and competing bacteria. S. coelicolor has evolved to survive in this varied environment by secreting an estimated 819 compounds, such as proteins and enzymes, that help it suck nutrients from the ground.

Camilla Kao, a Stanford University chemical engineer who has studied S. coelicolor, says knowing the microbe's genome should be a boon to drug makers. For while the bug is a prolific producer of antibiotics, it does so only under certain circumstances: when colonies of the bacteria are starving.

"That's a little bit difficult to control [in the lab]," Kao says. "It would be great if people could understand what triggers it at a molecular and genetic level. Then they could engineer it, or change the conditions and trick them into" making their natural drugs. "It would make antibiotic production more robust in an industrial setting."

C. Richard Hutchinson, a S. coelicolor expert and vice president of new technologies at Kosan Biosciences in California, agrees that knowing the S. coelicolor genome would help his firm and others like it in their efforts to generate new therapies. The organism "is where everybody goes to ask their questions about the biology" of the actinomyces, he explains.

Kosan has a novel anti-cancer drug that it's producing in the germ. That compound is in pre-clinical development and is at least a year away from being tested in people, Hutchinson says.

What To Do: For more on Streptomyces coelicolor, check out Stanford University or the Streptomyces coelicolor Investigating Gene Function Initiative Home Page.

SOURCES: Sir David Hopwood, Ph.D., John Innes Center, Norwich, England; Camilla Kao, Ph.D., assistant professor, chemical engineering, Stanford University, Stanford, Calif.; C. Richard Hutchinson, Ph.D., vice president, new technologies, Kosan Biosciences, Hayward, Calif.; May 9, 2002, Nature
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