Charting an Unexplored Streptococcal Biosynthetic Landscape Reveals a Unique Peptide Cyclization Motif

Abstract

Peptide natural products are often used as signals or antibiotics and contain unusual structural modifications, thus providing opportunities for expanding our understanding of Nature's therapeutic and biosynthetic repertoires. Herein, we have investigated the under-explored biosynthetic potential of Streptococci, prevalent bacteria in mammalian microbiomes that include mutualistic, commensal, and pathogenic members. Using a new bioinformatic search strategy, in which we linked the versatile radical Sadenosylmethionine (RaS) enzyme superfamily to an emerging class of natural products in the context of quorum sensing control, we identified numerous, uncharted biosynthetic loci. Focusing on one such locus, we identified an unprecedented posttranslational modification, consisting of a tetrahydro [5,6]benzindole cyclization motif in which four unactivated positions are linked by two C−C bonds in a regio-and stereospecific manner by a single RaS enzyme. Our results expand the scope of reactions that microbes have at their disposal in concocting complex ribosomal peptides.

The manifold roles of microbial ribosomal peptide–based natural products in physiology and ecology

“…SHP/Rgg system) (175)(176)(177). Genome-mining efforts identified a large panel of streptide-like biosynthetic systems in streptococci, all likely within the context of QS control (178). Biochemical characterization of these radical SAM enzymes led to the discovery of novel cyclization motifs such as ␤-thioether and ␣-ether linkages (179,180).…”

The SCIFF‐Derived Ranthipeptides Participate in Quorum Sensing in Solventogenic Clostridia

“…[ 33 ] Recently, it has been proposed that many other RiPPs such as streptide, likely participate in quorum sensing, as the biosynthetic gene clusters of these peptides are co‐transcribed with the well‐characterized shg/rgg system. [ 34,35 ] However, whether these RiPPs indeed participate in quorum sensing remains to be determined. In this study, we investigate the biological function of the SCIFF‐derived ranthipetides in two solventogenic clostridia.…”

RRE-Finder: A Genome-Mining Tool for Class-Independent RiPP Discovery

“…At this cutoff, most of the RREs found within the MIBiG set by precision mode were also found by exploratory mode (101/117, Figure 3). Only the RREs of linear-azol(in)e containing peptides (LAPs) 4 , streptides 39 , and polytheonamides 40 proved more difficult to detect by exploratory mode (Table S6). Further enriching the exploratory mode training set with RREs from these RiPP classes restored detection of the RREs from the polytheonamide cluster, although precision mode proved most consistent for RRE detection within the LAP and streptide classes.…”

“…Virtually no novel RiPP classes have been discovered using solely a bioinformatic approach: The ranthipeptide class was defined solely using bioinformatics, however this class had previously been predicted and misclassified as sactipeptides 25 . Furthermore, bioinformatics have been used to vastly expand known diversity within some classes-for example, the streptide class has been expanded to include enzymes that diverge from the class-defining Lys-Trp crosslinking enzymes 39,46 . Recently, two new RiPP classes-the peptide amino-acyl tRNA ligases (PEARLs) and the α-keto β-amino acid-containing peptides-were discovered through bioinformatic means 47,48 .…”