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

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