Streptococcal natural products mediate interspecies competition with Gram-positive bacterial pathogens

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, kill vancomycin-resistant Enterococcus and other Gram-positive bacteria, including Staphylococcus epidermidis, and methicillin-resistant Staphylococcus aureus. Further, inhibition of Gram-positive bacteria by some strains of S. mutans requires the production of the non-ribosomal cyclic lipopeptide mutanobactin, while another strain inhibits independent of mutanobactin. We determined that S. mutans mutanobactin production increases target cell membrane permeability and that killing is contact-dependent. We also determined that an E. faecalis virulence factor, the secreted protease gelatinase (GelE), is required for recovery from mutanobactin-mediated killing. Additionally, data show that S. mutans mutanobactin production prevents and kills E. faecalis biofilms. 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 root canal infection isolate. 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 killing, 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.