Discovery and Biosynthesis of Streptosactin, a Sactipeptide with an Alternative Topology Encoded by Commensal Bacteria in the Human Microbiome. Author Leah Bushin, Brett Covington, Britta Rued, Michael Federle, Mohammad Seyedsayamdost Publication Year 2020 Type Journal Article Abstract Mammalian microbiomes encode thousands of biosynthetic gene clusters (BGCs) and represent a new frontier in natural product research. We recently found an abundance of quorum sensing-regulated BGCs in mammalian microbiome streptococci that code for ribosomally synthesized and post-translationally modified peptides (RiPPs) and contain one or more radical S-adenosylmethionine (RaS) enzymes, a versatile superfamily known to catalyze some of the most unusual reactions in biology. In the current work, we target a widespread group of streptococcal RiPP BGCs and elucidate both the reaction carried out by its encoded RaS enzyme and identify its peptide natural product, which we name streptosactin. Streptosactin is the first sactipeptide identified from spp.; it contains two sequential four amino acid sactionine macrocycles, an unusual topology for this compound family. Bioactivity assays reveal potent but narrow-spectrum activity against the producing strain and its closest relatives that carry the same BGC, suggesting streptosactin may be a long-suspected fratricidal agent of . Our results highlight mammalian streptococci as a rich source of unusual enzymatic chemistries and bioactive natural products. Keywords Molecular Structure, Humans, Microbiota, Pore Forming Cytotoxic Proteins, Streptococcus thermophilus Journal J Am Chem Soc Volume 142 Issue 38 Pages 16265-16275 Date Published 2020 Sep 23 ISSN Number 1520-5126 DOI 10.1021/jacs.0c05546 Alternate Journal J Am Chem Soc PMID 32845143 PubMedGoogle ScholarBibTeXEndNote X3 XML