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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Accessions

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.

References

  1. 1.

    Antibiotics: Actions, Origins, Resistance (American Society for Microbiology Press, 2003)

  2. 2.

    & Antibiotics for emerging pathogens. Science 325, 1089–1093 (2009)

  3. 3.

    , & The evolving role of chemical synthesis in antibacterial drug discovery. Angew. Chem. Int. Ed. 53, 8840–8869 (2014)

  4. 4.

    et al. Ilotycin, a new antibiotic. Antibiot. Chemother. 2, 281–283 (1952)

  5. 5.

    et al. Asymmetric total synthesis of erythromycin. 3. Total synthesis of erythromycin. J. Am. Chem. Soc. 103, 3215–3217 (1981)

  6. 6.

    , , , & The asymmetric synthesis of erythromycin B. J. Am. Chem. Soc. 119, 3193–3194 (1997)

  7. 7.

    & Total synthesis of azithromycin. Angew. Chem. Int. Ed. 48, 1827–1829 (2009)

  8. 8.

    Total synthesis of desmethyl macrolide antibiotics. Synlett 26, 2199–2215 (2015)

  9. 9.

    Harnessing the biosynthetic potential of modular polyketide synthases. Chem. Rev. 97, 2577–2590 (1997)

  10. 10.

    , & Harnessing the biosynthetic code: combinations, permutations, and mutations. Science 282, 63–68 (1998)

  11. 11.

    et al. Engineering broader specificity into an antibiotic-producing polyketide synthase. Science 279, 199–202 (1998)

  12. 12.

    et al. Genetic engineering of macrolide biosynthesis: past advances, current state, and future prospects. Appl. Microbiol. Biotechnol. 85, 1227–1239 (2010)

  13. 13.

    , , & Acid degradation of erythromycin A and erythromycin B. Experientia 27, 362 (1971)

  14. 14.

    et al. Synthesis, in vitro and in vivo activity of novel 9-deoxo-9a-aza-9a-homoerythromycin A derivatives – a new class of macrolide antibiotics, the azalides. J. Antibiot. (Tokyo) 41, 1029–1047 (1988)

  15. 15.

    , , & Chemical modification of erythromycins. 1. Synthesis and antibacterial activity of 6-O-methylerythromycins-A. J. Antibiot. (Tokyo) 37, 187–189 (1984)

  16. 16.

    Methods for treating gastrointestinal diseases. WO patent 2010/048599 (2010)

  17. 17.

    , , , & CEM-101, a novel fluoroketolide: antimicrobial activity against a diverse collection of Gram-positive and Gram-negative bacteria. Diagn. Microbiol. Infect. Dis. 66, 393–401 (2010)

  18. 18.

    Mechanisms of resistance to macrolides and lincosamides: nature of the resistance elements and their clinical implications. Clin. Infect. Dis. 34, 482–492 (2002)

  19. 19.

    & Macrolide antibiotics: binding site, mechanism of action, resistance. Curr. Top. Med. Chem. 3, 949–961 (2003)

  20. 20.

    , & in Antibiotic Discovery and Development (eds & ) 455–484 (Springer, 2012)

  21. 21.

    Ketolides-telithromycin, an example of a new class of antibacterial agents. Clin. Microbiol. Infect. 6, 661–669 (2000)

  22. 22.

    et al. The ketolides: a critical review. Drugs 62, 1771–1804 (2002)

  23. 23.

    et al. Spectrum and mode of action of azithromycin (CP-62,993), a new 15-membered-ring macrolide with improved potency against Gram-negative organisms. Antimicrob. Agents Chemother. 31, 1939–1947 (1987)

  24. 24.

    et al. Pharmacokinetic and in vivo studies with azithromycin (CP-62,993), a new macrolide with an extended half-life and excellent tissue distribution. Antimicrob. Agents Chemother. 31, 1948–1954 (1987)

  25. 25.

    & Synthesis of 6-O-methyl-azithromycin and its ketolide analog via Beckmann rearrangement of 9(E)-6-O-methyl-erythromycin oxime. Bioorg. Med. Chem. Lett. 8, 2427–2432 (1998)

  26. 26.

    & A new, highly efficient, selective methodology for formation of medium-ring and macrocyclic lactones via intramolecular ketene trapping: an application to a convergent synthesis of (–)-kromycin. J. Am. Chem. Soc. 111, 8286–8288 (1989)

  27. 27.

    & Studies directed toward the synthesis of naturally occurring acyltetramic acids. 2. Preparation of the macrocyclic subunit of ikarugamycin. J. Org. Chem. 51, 5486–5489 (1986)

  28. 28.

    et al. Asymmetric total synthesis of erythromycin. 2. Synthesis of an erythronolide A lactone system. J. Am. Chem. Soc. 103, 3213–3215 (1981)

  29. 29.

    , , & A stepwise Huisgen cycloaddition process: copper(I)-catalyzed regioselective “ligation” of azides and terminal alkynes. Angew. Chem. Int. Ed. 41, 2596–2599 (2002)

  30. 30.

    et al. Structural insight into the antibiotic action of telithromycin against resistant mutants. J. Bacteriol. 185, 4276–4279 (2003)

  31. 31.

    , , & Structures of MLSBK antibiotics bound to mutated large ribosomal subunits provide a structural explanation for resistance. Cell 121, 257–270 (2005)

  32. 32.

    et al. Binding and action of CEM-101, a new fluoroketolide antibiotic that inhibits protein synthesis. Antimicrob. Agents Chemother. 54, 4961–4970 (2010)

  33. 33.

    , , & Revisiting the structures of several antibiotics bound to the bacterial ribosome. Proc. Natl Acad. Sci. USA 107, 17158–17163 (2010)

  34. 34.

    et al. Structural insights into species-specific features of the ribosome from the pathogen Staphylococcus aureus. Proc. Natl Acad. Sci. USA 112, E5805–E5814 (2015)

  35. 35.

    , & Practical protocols for the preparation of highly enantioenriched silyl ethers of (R)-3-hydroxypentan-2-one, building blocks for the synthesis of macrolide antibiotics. Synlett 27, 57–60 (2016)

  36. 36.

    , , , & Stereocontrolled synthesis of syn-β-hydroxy-α-amino acids by direct aldolization of pseudoephenamine glycinamide. Angew. Chem. Int. Ed. 53, 4642–4647 (2014)

  37. 37.

    , , & Enantioselective catalysis of ketoester-ene reaction of silyl enol ether to construct quaternary carbons by chiral dicationic palladium(II) complexes. J. Am. Chem. Soc. 129, 12950–12951 (2007)

  38. 38.

    , & New aldol type reaction. Chem. Lett. 2, 1011–1014 (1973)

  39. 39.

    , & An efficient directed Claisen reaction allows for rapid construction of 5,6-disubstituted 1,3-dioxin-4-ones. Synthesis 47, 2709–2712 (2015)

  40. 40.

    & Desosamino derivatives of macrolides as immunosuppressants and antifungal agents. WO patent 1993018042 (1993)

  41. 41.

    , & Synthesis of D-desosamine and analogs by rapid assembly of 3-amino sugars. Angew. Chem. Int. Ed. 55, 523–527 (2016)

  42. 42.

    & Synthesis of (R)-[2-2H]isopentenyl diphosphate and determination of its enantiopurity by 2H NMR spectroscopy in a lyotropic medium. Org. Lett. 1, 1067–1070 (1999)

  43. 43.

    & An efficient and general method for the synthesis of α,ω-difunctional reduced polypropionates by Zr-catalyzed asymmetric carboalumination: synthesis of the scyphostatin side chain. Angew. Chem. Int. Ed. 43, 2911–2914 (2004)

  44. 44.

    , & An efficient chemo-enzymatic approach to the enantioselective synthesis of 2-methyl-1,3-propanediol derivatives. Tetrahedr. Lett. 31, 5657–5660 (1990)

  45. 45.

    , , & Use of an ephedrine alkoxide to mediate enantioselective addition of an acetylide to a prochiral ketone: asymmetric synthesis of the reverse transcriptase inhibitor L-743,726. Tetrahedr. Lett. 36, 8937–8940 (1995)

  46. 46.

    , , , & Specific hydromagnesiation of prop-2-ynylic alcohols. A simple and specific route to terpenoids. J. Chem. Soc. Chem. Commun. 718–720 (1981)

  47. 47.

    et al. Ketolide antibacterials. US patent 6,590,083 (2003)

  48. 48.

    Antibiotic Resistance Threats in the United States, 2013. (CDC, US Dept Health and Human Services, 2013)

  49. 49.

    , , , & A convergent enantioselective route to structurally diverse 6-deoxytetracycline antibiotics. Science 308, 395–398 (2005)

  50. 50.

    & Development of a platform for the discovery and practical synthesis of new tetracycline antibiotics. Curr. Opin. Chem. Biol. 32, 48–57 (2016)

Download references

Acknowledgements

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.

Author information

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.

Affiliations

  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

Authors

  1. Search for Ian B. Seiple in:

  2. Search for Ziyang Zhang in:

  3. Search for Pavol Jakubec in:

  4. Search for Audrey Langlois-Mercier in:

  5. Search for Peter M. Wright in:

  6. Search for Daniel T. Hog in:

  7. Search for Kazuo Yabu in:

  8. Search for Senkara Rao Allu in:

  9. Search for Takehiro Fukuzaki in:

  10. Search for Peter N. Carlsen in:

  11. Search for Yoshiaki Kitamura in:

  12. Search for Xiang Zhou in:

  13. Search for Matthew L. Condakes in:

  14. Search for Filip T. Szczypiński in:

  15. Search for William D. Green in:

  16. Search for Andrew G. Myers in:

Contributions

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.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Text and Data – see contents page for details.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nature17967

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.