title: Siamycin attenuates fsr quorum sensing mediated by a gelatinase biosynthesis-activating pheromone in Enterococcus faecalis.
abstract: The expression of two Enterococcus faecalis virulence-related proteases, gelatinase (GelE) and serine protease (SprE), is positively regulated by a quorum-sensing system encoded by the fsr gene cluster. In this system, E. faecalis secretes an autoinducing peptide, gelatinase biosynthesis-activating pheromone (GBAP), which triggers the FsrC-FsrA two-component regulatory system controlling the expression of two transcripts, fsrBDC and gelE-sprE. In the present study, we screened actinomycete metabolites for inhibitors of fsr quorum sensing. E. faecalis was cultured with each actinomycete culture supernatant tested, and the production of gelatinase and the production of GBAP were examined using the first screening and the second screening, respectively. Culture supernatant of Streptomyces sp. strain Y33-1 had the most potent inhibitory effect on both gelatinase production and GBAP production without inhibiting E. faecalis cell growth. The inhibitor in the culture supernatant was identified as a known peptide antibiotic, siamycin I. Siamycin I inhibited both gelatinase production and GBAP production at submicromolar concentrations, and it inhibited E. faecalis cell growth at concentrations above micromolar concentrations. Quantitative analysis of fsrBDC and gelE-sprE transcripts revealed that siamycin I suppressed the expression of both transcripts at a sublethal concentration. Siamycin I attenuated gelatinase production even when an overdose of GBAP was exogenously added to the culture. These results suggested that siamycin I inhibited the GBAP signaling via the FsrC-FsrA two-component regulatory system in a noncompetitive manner. The sublethal concentrations of siamycin I also attenuated biofilm formation. Treatment with siamycin could be a novel means of treating enterococcal infections.
authors.affiliation: Department of Bioscience and Biotechnology, Faculty of Agriculture, Graduate School, Kyushu University, 6-10-1, Hakozaki, Fukuoka, Japan. nakayama@agr.kyushu-u.ac.jp
authors.forename: Jiro
authors.initials: J
authors.lastname: Nakayama
authors.forename: Emi
authors.initials: E
authors.lastname: Tanaka
authors.forename: Reiko
authors.initials: R
authors.lastname: Kariyama
authors.forename: Koji
authors.initials: K
authors.lastname: Nagata
authors.forename: Kenzo
authors.initials: K
authors.lastname: Nishiguchi
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Mitsuhata
authors.forename: Yumi
authors.initials: Y
authors.lastname: Uemura
authors.forename: Masaru
authors.initials: M
authors.lastname: Tanokura
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kumon
authors.forename: Kenji
authors.initials: K
authors.lastname: Sonomoto
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D018441:Biofilms; D013293:Enterococcus faecalis / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D036341:Intercellular Signaling Peptides and Proteins; D007783:Lactones / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000235:genetics / Q000378:metabolism*; D053038:Quorum Sensing; D014158:Transcription, Genetic
chemical_list: C409033:AgrCfs protein, Enterococcus faecalis; D001426:Bacterial Proteins; C409031:FsrA protein, Enterococcus faecalis; D036341:Intercellular Signaling Peptides and Proteins; D007783:Lactones; D010455:Peptides; D010456:Peptides, Cyclic; C438382:gelatinase biosynthesis-activating pheromone; C094260:siamycin I