Streptococcal mutanobactin mediates interspecies competition with gram-positive bacteria

Polymicrobial communities where bacteria must compete with each other to persist can serve as a source of uncharacterized antibacterial compounds to develop drugs for the treatment of drug-resistant infections. This study investigates interbacterial competition between bacteria found in the oral cavity, where Streptococcus species comprise a large portion of the resident oral microbiota, and Enterococcus faecalis is a pathobiont that is commonly found in root canal infections. We used co-cultures to determine whether oral streptococci and E. faecalis compete with each other. Our experiments revealed that multiple strains of Streptococcus mutans, an important cariogenic bacterium, reduce the viability of vancomycin-resistant Enterococcus and other gram-positive bacteria, including Staphylococcus epidermidis and methicillin-resistant Staphylococcus aureus. Furthermore, reduction in viability of bacteria by some strains of S. mutans requires the production of the non-ribosomal cyclic lipopeptide mutanobactin, while another strain inhibits independently of mutanobactin. We determined that S. mutans mutanobactin production increases target cell membrane permeability and that reduction of target cell viability is contact dependent. We also determined that the secreted E. faecalis protease gelatinase (GelE) is required for recovery from mutanobactin-mediated reduction in viability. Additionally, our data show that S. mutans mutanobactin production prevents E. faecalis biofilm formation and kills biofilm-associated E. faecalis. Together, this work demonstrates how natural products from a common oral bacterium contribute to competition in polymicrobial environments, which will inform future strategies to treat and prevent bacterial infections.IMPORTANCEAntimicrobial resistance requires new therapeutics to treat drug-resistant infections. Novel antimicrobial compounds can be discovered in polymicrobial communities, where bacterial natural products promote competitive fitness. The oral cavity hosts a microbial consortium, and we investigated interactions between oral streptococci and Enterococcus faecalis, a common cause of root canal infections. We demonstrate antibacterial activity of streptococcal mutanobactin against gram-positive pathogens, including antibiotic-resistant isolates. We further show that the E. faecalis virulence factor gelatinase promotes recovery from mutanobactin-mediated reduction in viability, and that mutanobactin prevents and kills E. faecalis biofilms. By probing interactions between bacteria that occupy the same niche and characterizing antibacterial activity of a bacterial product, this work contributes to broader efforts to identify and develop antibiotics to treat clinically relevant drug-resistant infections.