Pattern-Based\nGenome Mining Guides Discovery of the\nAntibiotic Indanopyrrole A from a Marine Streptomycete

Terrestrial actinomycetes in the genus <i>Streptomyces</i> have long been recognized as prolific producers of small-molecule\nnatural products, including many clinically important antibiotics\nand cytotoxic agents. Although Streptomyces can also be isolated from marine environments, their potential for\nnatural product biosynthesis remains underexplored. The MAR4 clade\nof largely marine-derived Streptomyces has been a rich source of novel halogenated natural products of\ndiverse structural classes. To further explore the biosynthetic potential\nof this group, we applied pattern-based genome mining, leading to\nthe discovery of the first halogenated pyrroloketoindane natural products,\nindanopyrrole A (<b>1</b>) and B (<b>2</b>), and the bioinformatic\nlinkage of these compounds to an orphan biosynthetic gene cluster\n(BCG) in 20 MAR4 genomes. Indanopyrrole A displays potent broad-spectrum\nantibiotic activity against clinically relevant pathogens. A comparison\nof the putative indanopyrrole BGC with that of the related compound\nindanomycin provides new insights into the terminal cyclization and\noffloading mechanisms in pyrroloketoindane biosynthesis. Broader searches\nof public databases reveal the rarity of this BGC while also highlighting\nopportunities for discovering additional compounds in this uncommon\nclass.