Streptococcus mutansinhibits the growth ofEnterococcusvia the non-ribosomal cyclic peptide mutanobactin

Abstract

AbstractEnterococcus faecalisis a Gram-positive commensal bacterium in the gastrointestinal tract and an opportunistic pathogen. Enterococci are a leading cause of nosocomial infections, treatment of which is complicated by intrinsic and acquired antibiotic resistance mechanisms. Additionally,E. faecalishas been associated with various oral diseases, and it is frequently implicated in the failure of endodontic treatment. For establishment and persistence in a microbial community,E. faecalismust successfully compete against other bacteria. Streptococcal species play an important role in the establishment of the oral microbiome and co-exist withEnterococcusin the small intestine, yet the nature of interactions betweenE. faecalisand oral streptococci remains unclear. Here, we describe a mechanism by whichStreptococcus mutansinhibits the growth ofE. faecalisand other Gram-positive pathogens through the production of mutanobactin, a cyclic lipopeptide. Mutanobactin is produced by a polyketide synthase–nonribosomal peptide synthetase hybrid system encoded by themublocus. Mutanobactin-producingS. mutansinhibits planktonic and biofilm growth ofE. faecalisand is also active against otherEnterococcusspecies andStaphylococcus aureus. Mutanobactin damages the cell envelope ofE. faecalis, similar to other lipopeptide antibiotics like daptomycin.E. faecalisresistance to mutanobactin is mediated by the virulence factor gelatinase, a secreted metalloprotease. Our results highlight the anti-biofilm potential of the microbial natural product mutanobactin, provide insight into howE. faecalisinteracts with other organisms in the human microbiome, and demonstrate the importance of studyingE. faecalisdynamics within polymicrobial communities.SignificanceEntercoccus faecalisis a leading cause of hospital-acquired infections, treatment of which is complicated by virulence factors, biofilm formation, and antibiotic resistance. Here, we demonstrate the antibiotic and anti-biofilm activity of mutanobactin, a cyclic lipopeptide produced byStreptococcus mutans, againstEnterococcusandStaphylococcusspp., including vancomycin-resistant Enterococci (VRE). Similar to other lipopeptides, mutanobactin damages the bacterial cell envelope.E. faecalismay overcome antagonism from mutanobactin through production of gelatinase, a secreted protease and prevalent virulence factor. Our results demonstrate the antibiotic and anti-biofilm potential of mutanobactin and highlight the role of bacterial proteases in resistance to bacteria- and host-derived antimicrobial compounds.