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A platform for the discovery of new macrolide antibiotics

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  • Ian B. Seiple

    (Harvard University
    †Present addresses: Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158, USA (I.B.S.); Novartis Pharma AG, Chemical and Analytical Development, CH-4002 Basel, Switzerland (A.L.-M.); McKinsey and Company, 55 East 52nd Street, 21st Floor, New York, New York 10022, USA (P.M.W.); Bayer Pharma AG, Medicinal Chemistry, Müllerstrasse 178, 13353 Berlin, Germany (D.T.H.); Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd, Shinagawa R&D Center, 1-2-58 Hiromachi, Shinagawa, Tokyo 140-8710, Japan (K.Y.); Department of Chemistry and Biomolecular Science, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan (Y.K.); Department of Chemistry, University of California, Berkeley, California 94720, USA (M.L.C.); Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK (F.T.S.); Trinity College, University of Cambridge, Cambridge CB2 1TQ, UK (W.D.G.).)

  • Ziyang Zhang

    (Harvard University)

  • Pavol Jakubec

    (Harvard University)

  • Audrey Langlois-Mercier

    (Harvard University
    †Present addresses: Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158, USA (I.B.S.); Novartis Pharma AG, Chemical and Analytical Development, CH-4002 Basel, Switzerland (A.L.-M.); McKinsey and Company, 55 East 52nd Street, 21st Floor, New York, New York 10022, USA (P.M.W.); Bayer Pharma AG, Medicinal Chemistry, Müllerstrasse 178, 13353 Berlin, Germany (D.T.H.); Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd, Shinagawa R&D Center, 1-2-58 Hiromachi, Shinagawa, Tokyo 140-8710, Japan (K.Y.); Department of Chemistry and Biomolecular Science, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan (Y.K.); Department of Chemistry, University of California, Berkeley, California 94720, USA (M.L.C.); Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK (F.T.S.); Trinity College, University of Cambridge, Cambridge CB2 1TQ, UK (W.D.G.).)

  • Peter M. Wright

    (Harvard University
    †Present addresses: Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158, USA (I.B.S.); Novartis Pharma AG, Chemical and Analytical Development, CH-4002 Basel, Switzerland (A.L.-M.); McKinsey and Company, 55 East 52nd Street, 21st Floor, New York, New York 10022, USA (P.M.W.); Bayer Pharma AG, Medicinal Chemistry, Müllerstrasse 178, 13353 Berlin, Germany (D.T.H.); Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd, Shinagawa R&D Center, 1-2-58 Hiromachi, Shinagawa, Tokyo 140-8710, Japan (K.Y.); Department of Chemistry and Biomolecular Science, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan (Y.K.); Department of Chemistry, University of California, Berkeley, California 94720, USA (M.L.C.); Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK (F.T.S.); Trinity College, University of Cambridge, Cambridge CB2 1TQ, UK (W.D.G.).)

  • Daniel T. Hog

    (Harvard University
    †Present addresses: Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158, USA (I.B.S.); Novartis Pharma AG, Chemical and Analytical Development, CH-4002 Basel, Switzerland (A.L.-M.); McKinsey and Company, 55 East 52nd Street, 21st Floor, New York, New York 10022, USA (P.M.W.); Bayer Pharma AG, Medicinal Chemistry, Müllerstrasse 178, 13353 Berlin, Germany (D.T.H.); Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd, Shinagawa R&D Center, 1-2-58 Hiromachi, Shinagawa, Tokyo 140-8710, Japan (K.Y.); Department of Chemistry and Biomolecular Science, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan (Y.K.); Department of Chemistry, University of California, Berkeley, California 94720, USA (M.L.C.); Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK (F.T.S.); Trinity College, University of Cambridge, Cambridge CB2 1TQ, UK (W.D.G.).)

  • Kazuo Yabu

    (Harvard University
    †Present addresses: Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158, USA (I.B.S.); Novartis Pharma AG, Chemical and Analytical Development, CH-4002 Basel, Switzerland (A.L.-M.); McKinsey and Company, 55 East 52nd Street, 21st Floor, New York, New York 10022, USA (P.M.W.); Bayer Pharma AG, Medicinal Chemistry, Müllerstrasse 178, 13353 Berlin, Germany (D.T.H.); Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd, Shinagawa R&D Center, 1-2-58 Hiromachi, Shinagawa, Tokyo 140-8710, Japan (K.Y.); Department of Chemistry and Biomolecular Science, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan (Y.K.); Department of Chemistry, University of California, Berkeley, California 94720, USA (M.L.C.); Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK (F.T.S.); Trinity College, University of Cambridge, Cambridge CB2 1TQ, UK (W.D.G.).)

  • Senkara Rao Allu

    (Harvard University)

  • Takehiro Fukuzaki

    (Harvard University)

  • Peter N. Carlsen

    (Harvard University)

  • Yoshiaki Kitamura

    (Harvard University
    †Present addresses: Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158, USA (I.B.S.); Novartis Pharma AG, Chemical and Analytical Development, CH-4002 Basel, Switzerland (A.L.-M.); McKinsey and Company, 55 East 52nd Street, 21st Floor, New York, New York 10022, USA (P.M.W.); Bayer Pharma AG, Medicinal Chemistry, Müllerstrasse 178, 13353 Berlin, Germany (D.T.H.); Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd, Shinagawa R&D Center, 1-2-58 Hiromachi, Shinagawa, Tokyo 140-8710, Japan (K.Y.); Department of Chemistry and Biomolecular Science, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan (Y.K.); Department of Chemistry, University of California, Berkeley, California 94720, USA (M.L.C.); Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK (F.T.S.); Trinity College, University of Cambridge, Cambridge CB2 1TQ, UK (W.D.G.).)

  • Xiang Zhou

    (Harvard University)

  • Matthew L. Condakes

    (Harvard University
    †Present addresses: Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158, USA (I.B.S.); Novartis Pharma AG, Chemical and Analytical Development, CH-4002 Basel, Switzerland (A.L.-M.); McKinsey and Company, 55 East 52nd Street, 21st Floor, New York, New York 10022, USA (P.M.W.); Bayer Pharma AG, Medicinal Chemistry, Müllerstrasse 178, 13353 Berlin, Germany (D.T.H.); Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd, Shinagawa R&D Center, 1-2-58 Hiromachi, Shinagawa, Tokyo 140-8710, Japan (K.Y.); Department of Chemistry and Biomolecular Science, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan (Y.K.); Department of Chemistry, University of California, Berkeley, California 94720, USA (M.L.C.); Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK (F.T.S.); Trinity College, University of Cambridge, Cambridge CB2 1TQ, UK (W.D.G.).)

  • Filip T. Szczypiński

    (Harvard University
    †Present addresses: Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158, USA (I.B.S.); Novartis Pharma AG, Chemical and Analytical Development, CH-4002 Basel, Switzerland (A.L.-M.); McKinsey and Company, 55 East 52nd Street, 21st Floor, New York, New York 10022, USA (P.M.W.); Bayer Pharma AG, Medicinal Chemistry, Müllerstrasse 178, 13353 Berlin, Germany (D.T.H.); Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd, Shinagawa R&D Center, 1-2-58 Hiromachi, Shinagawa, Tokyo 140-8710, Japan (K.Y.); Department of Chemistry and Biomolecular Science, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan (Y.K.); Department of Chemistry, University of California, Berkeley, California 94720, USA (M.L.C.); Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK (F.T.S.); Trinity College, University of Cambridge, Cambridge CB2 1TQ, UK (W.D.G.).)

  • William D. Green

    (Harvard University
    †Present addresses: Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158, USA (I.B.S.); Novartis Pharma AG, Chemical and Analytical Development, CH-4002 Basel, Switzerland (A.L.-M.); McKinsey and Company, 55 East 52nd Street, 21st Floor, New York, New York 10022, USA (P.M.W.); Bayer Pharma AG, Medicinal Chemistry, Müllerstrasse 178, 13353 Berlin, Germany (D.T.H.); Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd, Shinagawa R&D Center, 1-2-58 Hiromachi, Shinagawa, Tokyo 140-8710, Japan (K.Y.); Department of Chemistry and Biomolecular Science, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan (Y.K.); Department of Chemistry, University of California, Berkeley, California 94720, USA (M.L.C.); Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK (F.T.S.); Trinity College, University of Cambridge, Cambridge CB2 1TQ, UK (W.D.G.).)

  • Andrew G. Myers

    (Harvard University)

Abstract

The chemical modification of structurally complex fermentation products, a process known as semisynthesis, has been an important tool in the discovery and manufacture of antibiotics for the treatment of various infectious diseases. However, many of the therapeutics obtained in this way are no longer effective, because bacterial resistance to these compounds has developed. Here we present a practical, fully synthetic route to macrolide antibiotics by the convergent assembly of simple chemical building blocks, enabling the synthesis of diverse structures not accessible by traditional semisynthetic approaches. More than 300 new macrolide antibiotic candidates, as well as the clinical candidate solithromycin, have been synthesized using our convergent approach. Evaluation of these compounds against a panel of pathogenic bacteria revealed that the majority of these structures had antibiotic activity, some efficacious against strains resistant to macrolides in current use. The chemistry we describe here provides a platform for the discovery of new macrolide antibiotics and may also serve as the basis for their manufacture.

Suggested Citation

  • Ian B. Seiple & Ziyang Zhang & Pavol Jakubec & Audrey Langlois-Mercier & Peter M. Wright & Daniel T. Hog & Kazuo Yabu & Senkara Rao Allu & Takehiro Fukuzaki & Peter N. Carlsen & Yoshiaki Kitamura & Xi, 2016. "A platform for the discovery of new macrolide antibiotics," Nature, Nature, vol. 533(7603), pages 338-345, May.
    • Handle: RePEc:nat:nature:v:533:y:2016:i:7603:d:10.1038_nature17967
    DOI: 10.1038/nature17967
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    Cited by:

    1. Sebastián Serna-Loaiza & Angela Miltner & Martin Miltner & Anton Friedl, 2019. "A Review on the Feedstocks for the Sustainable Production of Bioactive Compounds in Biorefineries," Sustainability, MDPI, vol. 11(23), pages 1-24, November.
    2. Xiaokang Lv & Fen Su & Hongyan Long & Fengfei Lu & Yukun Zeng & Minghong Liao & Fengrui Che & Xingxing Wu & Yonggui Robin Chi, 2024. "Carbene organic catalytic planar enantioselective macrolactonization," Nature Communications, Nature, vol. 15(1), pages 1-7, December.
    3. Chih-Wei Chen & Nadja Leimer & Egor A. Syroegin & Clémence Dunand & Zackery P. Bulman & Kim Lewis & Yury S. Polikanov & Maxim S. Svetlov, 2023. "Structural insights into the mechanism of overcoming Erm-mediated resistance by macrolides acting together with hygromycin-A," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    4. Nunes E. L. C. & Novais J. S. & Silva A. C. J. A. & Guerra L. R. & Castro H. C., 2017. "The Future is Still Ahead: Methodologies for Discovering New Antimicrobials within the World Biodiversity," Journal of Biotechnology Research, Academic Research Publishing Group, vol. 3(1), pages 1-9, 01-2017.
    5. Darryl M. Wilson & Daniel J. Driedger & Dennis Y. Liu & Sandra Keerthisinghe & Adrian Hermann & Christoph Bieniossek & Roger G. Linington & Robert A. Britton, 2024. "Targeted sampling of natural product space to identify bioactive natural product-like polyketide macrolides," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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