Mix and match Streptomyces

Scientists have succeeded in turning Streptomyces into a system akin to combinatorial chemistry for producing molecular diversity. By mixing and matching enzyme domains in two Streptomyces polyketide synthases (PKSs)—6-deoxyerythronolide B synthase (DEBS) and rapamycin PKS—researchers at KOSAN Biosciences (Hayward, CA) have generated a library of >50 macrolides that would be impractical to produce by chemical methods. The modular nature of the DEBS enzyme allowed the KOSAN team to substitute corresponding domains from the rapamycin PKS encoding alternative substrate specificities. According to Robert McDaniel, lead author on the paper (PNAS 96, 1846–1851, 1999), engineered DEBS containing single, double, or triple catalytic domain substitutions catalyzed the production of erythromycin macrolactones with corresponding single, double, or triple modifications. "The relatively high success rate of the approach suggests that combinatorial mutations are well tolerated by the PKS," he says. "To my knowledge, this is the first demonstration that you can combine mutations in a polyketide synthase in a combinatorial fashion." Kosan is currently collaborating with Johnson & Johnson (New Brunswick, NJ) to apply the technology to novel antibacterial discovery as well as exploring opportunities in anticancer drugs, immunosuppressants, and agricultural products.

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Marshall, A. Mix and match Streptomyces. Nat Biotechnol 17, 317 (1999). https://doi.org/10.1038/7849

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