A platform for the discovery of new macrolide antibiotics

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...

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Published inNature (London) Vol. 533; no. 7603; pp. 338 - 345
Main Authors Seiple, Ian B, Zhang, Ziyang, Jakubec, Pavol, Langlois-Mercier, Audrey, Wright, Peter M, Hog, Daniel T, Yabu, Kazuo, Allu, Senkara Rao, Fukuzaki, Takehiro, Carlsen, Peter N, Kitamura, Yoshiaki, Zhou, Xiang, Condakes, Matthew L, Szczypiński, Filip T, Green, William D, Myers, Andrew G
Format Journal Article
LanguageEnglish
Published England Nature Publishing Group 19.05.2016
Subjects
Amino Sugars - chemical synthesis
Amino Sugars - chemistry
Amino Sugars - pharmacology
Anti-Bacterial Agents - chemical synthesis
Anti-Bacterial Agents - chemistry
Anti-Bacterial Agents - pharmacology
Antibiotics
Bacteria - drug effects
Chemical synthesis
Drug Discovery - methods
Humans
Infectious diseases
Ketolides - chemical synthesis
Ketolides - chemistry
Macrolides - chemical synthesis
Macrolides - chemistry
Macrolides - pharmacology
Methods
Microbial Sensitivity Tests
Molecular Structure
Production processes
R&D
Research & development
Small Molecule Libraries - chemical synthesis
Small Molecule Libraries - chemistry
Triazoles - chemical synthesis
Triazoles - chemistry
Triazoles - pharmacology
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Summary: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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These authors contributed equally to this work.
Present addresses: School of Pharmacy, University of California, San Francisco, California 94158, USA (I.B.S.); McKinsey & Company, 55 East 52nd Street, 21st Floor, New York, New York 10022, USA (P.M.W.); Novartis Pharma AG, Chemical and Analytical Development, CH-4002 Basel, Switzerland (A.L.); Bayer Pharma AG, Medicinal Chemistry, Müllerstr. 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, CA 94720, USA (M.L.C.); Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK (F.T.S.); Trinity College, Cambridge CB2 1TQ, UK (W.D.G.).
Author 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. 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., 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 analogs; 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.
ISSN:0028-0836
1476-4687
DOI:10.1038/nature17967