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.

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Data deposits

Atomic coordinates and structure factors for the crystal structure reported have been deposited with the Cambridge Crystallographic Database under accession number CCDC 1440650.


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We acknowledge funding from Alistair and Celine Mactaggart, from the Gustavus and Louise Pfeiffer Research Foundation, and from the Blavatnik Biomedical Accelerator Program at Harvard University. We thank NERCE (NIH project number U54 AI057159), W. Weiss (Univ. North Texas), and R. Alm and S. Lahiri (Macrolide Pharmaceuticals) for measuring MIC values, R. Alm and T. Dougherty (Harvard Medical School) for genetic characterization of a microbial resistance gene, and S.-L. Zheng (Harvard University) for conducting X-ray crystallographic analyses. I.B.S. acknowledges postdoctoral fellowship support from the National Institutes of Health (F32GM099233); Z.Z. is a Howard Hughes Medical Institute International Student Research fellow; A.L.-M. acknowledges postdoctoral fellowship support from the Swiss National Science Foundation (PBGEPE2-139864) and the Novartis Foundation; D.T.H. is indebted to the Deutsche Forschungsgemeinschaft (DFG) for a postdoctoral fellowship (HO 5326/1-1); T.F. acknowledges Daiichi-Sankyo Co., Ltd, for financial support; and Y.K. acknowledges support from the Engineering Promotion Fund of Gifu University.

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Author notes

    • Ian B. Seiple
    • , Audrey Langlois-Mercier
    • , Peter M. Wright
    • , Daniel T. Hog
    • , Kazuo Yabu
    • , Yoshiaki Kitamura
    • , Matthew L. Condakes
    • , Filip T. Szczypiński
    •  & William D. Green

    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.).

    • Ian B. Seiple
    •  & Ziyang Zhang

    These authors contributed equally to this work.


  1. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA

    • 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
    • , Xiang Zhou
    • , Matthew L. Condakes
    • , Filip T. Szczypiński
    • , William D. Green
    •  & Andrew G. Myers


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I.B.S., Z.Z. and A.G.M. identified the targets and designed the synthetic routes; I.B.S. and Z.Z. executed and optimized the synthetic routes described in the main text; I.B.S., Z.Z., P.J., P.M.W., A.L.-M. and D.T.H. executed the synthetic routes shown in the Extended Data; I.B.S., Z.Z., P.J., P.M.W., A.L.-M., D.T.H., K.Y., T.F., P.N.C., X.Z., M.L.C., F.T.S. and W.D.G. synthesized individual macrolide analogues; I.B.S., Z.Z., Y.K. and S.R.A. synthesized and scaled the building blocks. I.B.S., Z.Z. and A.G.M. wrote the paper. All authors discussed the results and commented on the manuscript.

Competing interests

I.B.S., Z.Z. and A.G.M. have filed three provisional patents and an international patent application: US 62/061571, ‘14-Membered Ketolides and Methods of Their Preparation and Use’; US 62/138198, ‘Macrolides with Modified Desosamine Sugars and Uses Thereof’; US 62/214774, ‘Right Half Synthesis of 14-Membered Azaketolides’; PCT/US2014/033025, ‘Macrolides and Methods of Their Preparation and Use’. A.G.M. declares that he is a founder, board member, and chairman of the scientific advisory board of Macrolide Pharmaceuticals, and Z.Z. and I.B.S. declare that they serve as scientific consultants to Macrolide Pharmaceuticals.

Corresponding author

Correspondence to Andrew G. Myers.

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