Heterologous Expression of Fluostatin Gene Cluster Leads to a Bioactive Heterodimer

The biosynthesis gene cluster (<i>fls</i>) for atypical angucycline fluostatins was identified from the marine derived <i>Micromonospora rosaria</i> SCSIO N160 and was confirmed by gene knockouts and the biochemical characterization of a bifunctional oxygenase FlsO2. The absolute configuration of the key biosynthetic intermediate prejadomycin was determined for the first time by Cu Kα X-ray analysis. Heterologous expression of the intact <i>fls</i>-gene cluster in <i>Streptomyces coelicolor</i> YF11 in the presence of 3% sea salts led to the isolation of two new compounds: fluostatin L (<b>1</b>) and difluostatin A (<b>2</b>). Difluostatin A (<b>2</b>), an unusual heterodimer, exhibited antibacterial activities