Streptococcus mutans inhibits the growth of Enterococcus via the non-ribosomal cyclic peptide mutanobactin

Enterococcus faecalis is 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. faecalis has 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. faecalis must successfully compete against other bacteria. Streptococcal species play an important role in the establishment of the oral microbiome and co-exist with Enterococcus in the small intestine, yet the nature of interactions between E. faecalis and oral streptococci remains unclear. Here, we describe a mechanism by which Streptococcus mutans inhibits the growth of E. faecalis and 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 the mub locus. Mutanobactin-producing S. mutans inhibits planktonic and biofilm growth of E. faecalis and is also active against other Enterococcus species and Staphylococcus aureus. Mutanobactin damages the cell envelope of E. faecalis, similar to other lipopeptide antibiotics like daptomycin. E. faecalis resistance 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 how E. faecalis interacts with other organisms in the human microbiome, and demonstrate the importance of studying E. faecalis dynamics within polymicrobial communities.