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Genetic engineering of aminodeoxyhexose biosynthesis in Streptomyces fradiae

Nature Biotechnology volume 20, pages 713–716 (2002)Cite this article

Abstract

The antibacterial properties of macrolide antibiotics (such as erythromycin, tylosin, and narbomycin) depend ultimately on the glycosylation of otherwise inactive polyketide lactones. Among the sugars commonly found in such macrolides are various 6-deoxyhexoses including the 3-dimethylamino sugars mycaminose and desosamine (4-deoxymycaminose). Some macrolides (such as tylosin) possess multiple sugar moieties, whereas others (such as narbomycin) have only single sugar substituents. As patterns of glycosylation markedly influence a macrolide's drug activity, there is considerable interest in the possibility of using combinatorial biosynthesis to generate new pairings of polyketide lactones with sugars, especially 6-deoxyhexoses. Here, we report a successful attempt to alter the aminodeoxyhexose-biosynthetic capacity of Streptomyces fradiae (a producer of tylosin) by importing genes from the narbomycin producer Streptomyces narbonensis. This engineered S. fradiae produced substantial amounts of two potentially useful macrolides that had not previously been obtained by fermentation.

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Figure 1
Figure 2
Figure 3: Fermentation products from S. fradiae supplemented with desosamine-biosynthetic genes from S. narbonensis. HPLC analysis of material produced by
Figure 4: Analysis of fermentation products by mass spectrometry.

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Acknowledgements

This work was supported by the UK Biotechnology and Biological Sciences Research Council, project grant 91/T08195.

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Authors and Affiliations

  1. Biochemistry Department, University of Leicester, Leicester, LE1 7RH, UK

    Andrew R. Butler, Neil Bate & Eric Cundliffe

  2. Elanco Animal Health R & D, Greenfield, 46140, IN

    Douglas E. Kiehl & Herbert A. Kirst

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  1. Andrew R. Butler
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  2. Neil Bate
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  3. Douglas E. Kiehl
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Correspondence to Eric Cundliffe.

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Butler, A., Bate, N., Kiehl, D. et al. Genetic engineering of aminodeoxyhexose biosynthesis in Streptomyces fradiae. Nat Biotechnol 20, 713–716 (2002). https://doi.org/10.1038/nbt0702-713

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