Dual quorum-sensing control of purine biosynthesis drives pathogenic fitness of Enterococcus faecalis

Enterococcus faecalis is a resident of the human gut, though upon translocation to the blood or body tissues, it can be pathogenic. Here we discover and characterize two peptide-based quorum-sensing systems that transcriptionally modulate de novo purine biosynthesis in E. faecalis . Using a comparative genomic analysis, we find that most enterococcal species do not encode this system; E. moraviensis , E. haemoperoxidus and E. caccae , three species that are closely related to E. faecalis , encode one of the two systems, and only E. faecalis encodes both systems. We show that these systems are important for the intracellular survival of E. faecalis within macrophages and for the fitness of E. faecalis in a murine wound infection model. Taken together, we combine comparative genomics, microbiological, bacterial genetics, transcriptomics, targeted proteomics and animal model experiments to describe a paired quorum sensing mechanism that directly influences central metabolism and impacts the pathogenicity of E. faecalis .