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Review
. 2017 May 3;18(5):960.
doi: 10.3390/ijms18050960.

Molecular Mechanism of Quorum-Sensing in Enterococcus Faecalis: Its Role in Virulence and Therapeutic Approaches

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Free PMC article
Review

Molecular Mechanism of Quorum-Sensing in Enterococcus Faecalis: Its Role in Virulence and Therapeutic Approaches

Liaqat Ali et al. Int J Mol Sci. .
Free PMC article

Abstract

Quorum-sensing systems control major virulence determinants in Enterococcusfaecalis, which causes nosocomial infections. The E. faecalis quorum-sensing systems include several virulence factors that are regulated by the cytolysin operon, which encodes the cytolysin toxin. In addition, the E. faecalis Fsr regulator system controls the expression of gelatinase, serine protease, and enterocin O16. The cytolysin and Fsr virulence factor systems are linked to enterococcal diseases that affect the health of humans and other host models. Therefore, there is substantial interest in understanding and targeting these regulatory pathways to develop novel therapies for enterococcal infection control. Quorum-sensing inhibitors could be potential therapeutic agents for attenuating the pathogenic effects of E. faecalis. Here, we discuss the regulation of cytolysin, the LuxS system, and the Fsr system, their role in E. faecalis-mediated infections, and possible therapeutic approaches to prevent E. faecalis infection.

Keywords: Enterococcus faecalis; Fsr; cytolysin; multidrug-resistant pathogen; quorum-sensing; quorum-sensing inhibitor; virulence factor.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The Fsr quorum-sensing system and its regulation in E. faecalis. The FsrD propeptide (encoded by fsrD) is exported and processed to produce small lactone gelatinase biosynthesis-activating pheromone (GBAP) via FsrB. FsrC is part of a two-component regulatory system that responds to extracellular GBAP and phosphorylates the intracellular response regulator, FsrA, which then induces the expression of ef1097, ef1097b, fsr locus, gelE (encoding a gelatinase), and sprE (encoding a serine protease). The pre-proprotein (170 amino acids) encoded by ef1097 is cleaved (N-terminal 34 amino acids are removed) and transported through the Sec-dependent pathway, where gelatinase further trims the precursor to form enterocin O16 (68 C-terminal amino acids). ZBzl-YAA5911 (competitively) and NaCl (concentration-dependently) inhibit the interaction of GBAP with FsrC. Ambuic acid inhibits FsrB activity. Siamycin I, Sviceucin, and WS9326A inhibit the phosphorylation of FsrC.
Figure 2
Figure 2
The cytolysin quorum-sensing system in E. faecalis. (A) The toxin structural components CylLL (larger subunit) and CylLS (smaller subunit) are encoded by cylLL and cylLS. CylLL and CylLS core peptides are post-translationally modified by CylM, after which these peptides are further processed and transported by CylB. Extracellular protease, CylA, removes six amino acid residues (leader peptide) from both CylLL and CylLS, making them active toxin subunits. The signal transduction mechanism linking the binding of extracellular CylLS to CylR1 at the membrane with the dissociation of CylR2 from the PL promoter is currently unknown. CylI provides self-immunity against cytolysin; (B) Structures of the CylLL and CylLS mature cytolysin subunits [82].
Figure 3
Figure 3
Structures of Fsr quorum-sensing system inhibitors: Siamycin I (IC50 approximately 100 nM) extracted from soil Streptomyces sp [109]; Sviceucin obtained from Streptomyces sviceus, (1 and 10 µM concentrations inhibited 50–70% and >90% of gelatinase production, respectively) [111]; ZBzl-YAA5911 is a synthetic inhibitor with an IC50 of 26.2 nM [113]; Ambuic acid (IC50 approximately 10 µM), extracted from fungal secondary metabolites [112]; and WS9326A (IC50 approximately 19 µM), extracted from a culture of actinomycetes [114].

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