Discovery of Polycyclic Macrolide Shuangdaolides by Heterologous Expression of a Cryptic <i>trans</i>-AT PKS Gene Cluster

Abstract

A cryptic <i>trans</i>-acyltransferase polyketide synthase biosynthetic gene cluster <i>sdl</i> (80 kb) from <i>Streptomyces</i> sp. B59 was cloned and transferred into a heterologous host <i>Streptomyces albus</i> J1074, resulting in a class of polycyclic macrolide shuangdaolides A-D (<b>1-4</b>) and dumulmycin (<b>5</b>). Heterologous expression and gene inactivation experiments allowed the identification of two biosynthetic intermediates, <b>6</b> and <b>7</b>, suggesting an unusual multidomain SDR oxidoreductase SdlR in charge of the formation of a rare 2-hydroxycyclopentenone moiety in this class of compounds.