Quorum Sensing in Streptococcus mutans Regulates Production of Tryglysin, a Novel RaS-RiPP Antimicrobial Compound

Abstract

The genus <i>Streptococcus</i> encompasses a large bacterial taxon that commonly colonizes mucosal surfaces of vertebrates and is capable of disease etiologies originating from diverse body sites, including the respiratory, digestive, and reproductive tracts. Identifying new modes of treating infections is of increasing importance, as antibiotic resistance has escalated. <i>Streptococcus mutans</i> is an important opportunistic pathogen that is an agent of dental caries and is capable of systemic diseases such as endocarditis. As such, understanding how it regulates virulence and competes in the oral niche is a priority in developing strategies to defend from these pathogens. We determined that <i>S. mutans</i> UA159 possesses a bona fide short hydrophobic peptide (SHP)/Rgg quorum-sensing system that regulates a specialized biosynthetic operon featuring a radical-SAM (<i>S</i>-adenosyl-l-methionine) (RaS) enzyme and produces a ribosomally synthesized and posttranslationally modified peptide (RiPP). The pairing of SHP/Rgg regulatory systems with RaS biosynthetic operons is conserved across streptococci, and a locus similar to that in <i>S. mutans</i> is found in <i>Streptococcus ferus</i>, an oral streptococcus isolated from wild rats. We identified the RaS-RiPP product from this operon and solved its structure using a combination of analytical methods; we term these RiPPs tryglysin A and B for the unusual Trp-Gly-Lys linkage. We report that tryglysins specifically inhibit the growth of other streptococci, but not other Gram-positive bacteria such as <i>Enterococcus faecalis</i> or <i>Lactococcus lactis</i> We predict that tryglysin is produced by <i>S. mutans</i> in its oral niche, thus inhibiting the growth of competing species, including several medically relevant streptococci.<b>IMPORTANCE</b> Bacteria interact and compete with a large community of organisms in their natural environment. <i>Streptococcus mutans</i> is one such organism, and it is an important member of the oral microbiota. We found that <i>S. mutans</i> uses a quorum-sensing system to regulate production of a novel posttranslationally modified peptide capable of inhibiting growth of several streptococcal species. We find inhibitory properties of a similar peptide produced by <i>S. ferus</i> and predict that these peptides play a role in interspecies competition in the oral niche.