A platform for the discovery of new macrolide antibiotics

作者：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; Szczypinski Filip T; Green William D; Myers Andrew G^*

来源：Nature, 2016, 533(7603): 338-+.

DOI：10.1038/nature17967

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.

• 出版日期2016-5-19