A platform for the discovery of new macrolide antibiotics

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 and Andrew G. Myers ()
Additional contact information
Ian B. Seiple: Harvard University
Ziyang Zhang: Harvard University
Pavol Jakubec: Harvard University
Audrey Langlois-Mercier: Harvard University
Peter M. Wright: Harvard University
Daniel T. Hog: Harvard University
Kazuo Yabu: Harvard University
Senkara Rao Allu: Harvard University
Takehiro Fukuzaki: Harvard University
Peter N. Carlsen: Harvard University
Yoshiaki Kitamura: Harvard University
Xiang Zhou: Harvard University
Matthew L. Condakes: Harvard University
Filip T. Szczypiński: Harvard University
William D. Green: Harvard University
Andrew G. Myers: Harvard University

Nature, 2016, vol. 533, issue 7603, 338-345

Abstract: 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.

Date: 2016
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DOI: 10.1038/nature17967

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