Kosan Biosciences Inc., a California start-up company, is touting anew collection of potential drug candidates with a variation on theold soft drink ads for the "uncola."

The fledgling firm in Burlingame, Calif., is practicing a technology,called combinatorial biosynthesis, to mine what it describes as"unnatural natural products" from traditional drug sources found insoil bacteria and other organisms.

Streptomyces, for example, is a soil bacteria with several hundredspecies that produce more than half of all antibiotics.

The drugs, said Kosan's CEO and co-founder, Daniel Santi, arepolyketides, or small organic molecules, synthesized by the bacteria.Polyketides made by other organisms, fungi and plants serve as anti-fungal and anti-cancer agents as well as immunosuppressant drugs.

Santi said about 10,000 polyketides that have been isolated in natureand drugs from those molecules generate $5 billion in sales eachyear.

Kosan's business is making new polyketides by generating variationsof those already isolated. The company is working to create librariesof genetically engineered molecules whose number will far exceedthat of polyketides found naturally.

"If you're looking for diamonds you have a better chance of findingthem in a diamond mine," said Santi, referring to the advantage ofcreating new drugs from proven therapeutic molecules.

Among those libraries of reconfigured polyketides, Kosan expects todiscover replacements for antibiotics, such as erythromycin, that havebecome ineffective against resistant bacterial infections.

The unique molecules, however, may also prove to be new drugsaltogether.

Kosan's technology was invented by the company's co-founder,Chaitan Khosla, an assistant professor of chemical engineering andchemistry at Stanford University in Palo Alto, Calif. Santi is aprofessor of biochemistry and pharmaceutical chemistry at theUniversity of California in San Francisco.

In combinatorial biosynthesis, Santi explained, new drug moleculesare made by genetically altering the gene clusters in an organism,such as Streptomyces, that synthesize polyketides. The modifiedgenes, produced in Escherichia coli, are reinserted in theStreptomyces where new polyketides are expressed.

To overcome the problem of bacterial resistance to antibiotics,chemical analogues to the natural molecules could be manufacturedfrom scratch, but the process, Santi said, is difficult because of thecomplexity of polyketides.

Kosan's "unnatural natural products" are analogues synthesized byrecombining genes in the organism itself.

"What Kosan does," Santi observed, "is accelerate the evolution ofnatural polyketide synthesis."

Kosan has created hundreds of new molecules, but Santi said, it willtake several years to build up libraries containing tens of thousands ofnew natural products. The company is seeking corporatecollaborations to support its efforts.

In the meantime, Kosan has received two Small Business InnovativeResearch grants from the National Institutes of Health in Bethesda,Md., to develop new versions of antibiotic and anti-cancer agents.

In May 1996, Kosan also received $3 million from a group ofinvestors that included Chiron Corp., of Emeryville, Calif. Chiron'sparticipation also involved a collaboration to screen Kosan'smodified polyketides against disease targets.

This is not the first time Santi and Khosla have tried tocommercialize the combinatorial biosynthesis.

They formed Parnassus Pharmaceuticals Inc., of Alameda, Calif.,with the help of biotechnology financier David Blech and his firm, D.Blech & Co., of New York. When Blech's investment companycollapsed, so did Parnassus. (See BioWorld Today, Oct. 10, 1994, p.1.)

Santi also was founder of another company, Protos Corp., which wasacquired in 1992 by Chiron and merged into its drug discoverygroup.

Kosan _ the name is a combination of Khosla and Santi _ hascurrent projects underway that include creating new polyketides forthe antibiotic, erythromycin; the anti-cancer drug, daunorubicin; andthe immunosuppressant, rapamycin. n

-- Charles Craig

(c) 1997 American Health Consultants. All rights reserved.

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