Gelatinase biosynthesis-activating pheromone: a peptide lactone that mediates a quorum sensing in Enterococcus faecalis

Biosynthesis of gelatinase, a virulence factor of Enterococcus faecalis, wa s found to be regulated in a cell density-dependent fashion in which its pr oduction is active in late log to early stationary phase. Addition of early stationary phase culture filtrate to medium shifted the onset of gelatinas e production to that of mid-log phase, suggesting that E. faecalis secretes a gelatinase biosynthesis-activating pheromone (GBAP). GBAP was isolated f rom culture supernatant of E. faecalis OG1S-P. Structural analysis suggeste d GBAP to be an 11-residue cyclic peptide containing a lactone structure, i n which the alpha -carboxyl group of the C-terminal amino acid is linked to a hydroxyl group of the serine of the third residue. A synthetic peptide p ossessing the deduced structure showed GBAP activity at nanomolar concentra tions as did natural GBAP. Database searches revealed that GBAP corresponds to a C-terminal part of a 242-residue FsrB protein. Northern analysis show ed that GBAP slowly induces the transcription of two operons, fsrB-fsrC enc oding FsrB and a putative histidine kinase FsrC and gelE-sprE encoding gela tinase GelE and serine protease SprE. Strains with an insertion mutation in either fsrC or a putative response regulator gene fsrA failed to respond t o GBAP, suggesting that the GBAP signal is transduced by a two-component re gulatory system.