IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v533y2016i7603d10.1038_nature17967.html
   My bibliography  Save this article

A platform for the discovery of new macrolide antibiotics

Author

Listed:
  • 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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/nature17967
    File Function: Abstract
    Download Restriction: Access to the full text of the articles in this series is restricted.
    File URL: https://libkey.io/10.1038/nature17967?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    As the access to this document is restricted, you may want to search for a different version of it.

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. 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.
    2. Cristina Herencias & Laura Álvaro-Llorente & Paula Ramiro-Martínez & Ariadna Fernández-Calvet & Ada Muñoz-Cazalla & Javier DelaFuente & Fabrice E. Graf & Laura Jaraba-Soto & Juan Antonio Castillo-Polo, 2024. "β-lactamase expression induces collateral sensitivity in Escherichia coli," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    3. 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.
    4. 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.
    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.
    6. Christopher J. Barden & Fan Wu & J. Pedro Fernandez-Murray & Erhu Lu & Shengguo Sun & Marcia M. Taylor & Annette L. Rushton & Jason Williams & Mahtab Tavasoli & Autumn Meek & Alla Siva Reddy & Lisa M., 2024. "Computer-aided drug design to generate a unique antibiotic family," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    7. 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.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:nature:v:533:y:2016:i:7603:d:10.1038_nature17967. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.