Production of ‘hybrid’ antibiotics by genetic engineering
D. A. Hopwood*, F. Malpartida*, H. M. Kieser*, H. Ikeda†, J. Duncan‡, I. Fujii‡, B. A. M. Rudd§∥, H. G. Floss‡ & S. Ōmura†
*John Innes Institute, Colney Lane, Norwich NR4 7UH, UK
†School of Pharmaceutical Sciences, Kitasato University and The Kitasato Institute, Tokyo 108, Japan
‡Department of Chemistry, Ohio State University, Columbus, Ohio 43210, USA
§Department of Medicinal Chemistry and Pharmacognosy, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907, USA
∥Present address: Glaxo Group Research, Greenford, Middlesex UB6 0HE, UK.
The recent development of molecular cloning systems in Streptomyces
1–4 has made possible the isolation of biosynthetic genes for some of the many antibiotics produced by members of this important genus of bacteria5–10. Such clones can now be used to test the idea that novel antibiotics could arise through the transfer of biosynthetic genes between streptomycetes producing different antibiotics11. The likelihood of a ‘hybrid’ compound being produced must depend on the substrate specificities of the biosynthetic enzymes, about which little is known. In attempts to demonstrate hybrid antibiotic production, we therefore began with strains producing different members of the same chemical class of compounds in order to maximize the chance of success. Here we report the production of novel compounds by gene transfer between strains producing the isochromanequinone antibiotics actinorhodin12, granaticin13 and medermycin14. These experiments were made possible by the recent cloning of the whole set of genes for the biosynthetic pathway of actinorhodin from Streptomyces coelicolor A3(2) (ref. 8). We believe that this represents the first report of the production of hybrid antibiotics by genetic engineering.
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