| Title: | A novel chemical inducer of Streptococcus quorum sensing acts by inhibiting the pheromone-degrading endopeptidase PepO |
| Author(s): | Perez Morales TG; Ratia K; Wang DS; Gogos A; Bloem L; Driver TG; Federle MJ; |
| Address: | "From the Center for Biomolecular Sciences, Department of Medicinal Chemistry and Pharmacognosy. the UIC High-throughput Screening Core Facility, and. the Departments of Chemistry and. Microbiology and Immunology, University of Illinois at Chicago, Chicago, Illinois 60607 and. UICentre for Drug Discovery, University of Illinois at Chicago the Institute of Next Generation Matter Transformation, College of Chemical Engineering, Huaqiao University, Xiamen, Fujian 361021, China. From the Center for Biomolecular Sciences, Department of Medicinal Chemistry and Pharmacognosy, mfederle@uic.edu" |
| ISSN/ISBN: | 1083-351X (Electronic) 0021-9258 (Print) 0021-9258 (Linking) |
| Abstract: | "Bacteria produce chemical signals (pheromones) to coordinate behaviors across a population in a process termed quorum sensing (QS). QS systems comprising peptide pheromones and their corresponding Rgg receptors are widespread among Firmicutes and may be useful targets for manipulating microbial behaviors, like suppressing virulence. The Rgg2/3 QS circuit of the human pathogen Streptococcus pyogenes controls genes affecting resistance to host lysozyme in response to short hydrophobic pheromones (SHPs). Considering that artificial activation of a QS pathway may be as useful in the objective of manipulating bacteria as inhibiting it, we sought to identify small-molecule inducers of the Rgg2/3 QS system. We report the identification of a small molecule, P516-0475, that specifically induced expression of Rgg2/3-regulated genes in the presence of SHP pheromones at concentrations lower than typically required for QS induction. In searching for the mode of action of P516-0475, we discovered that an S. pyogenes mutant deficient in pepO, a neprilysin-like metalloendopeptidase that degrades SHP pheromones, was unresponsive to the compound. P516-0475 directly inhibited recombinant PepO in vitro as an uncompetitive inhibitor. We conclude that this compound induces QS by stabilizing SHP pheromones in culture. Our study indicates the usefulness of cell-based screens that modulate pathway activities to identify unanticipated therapeutic targets contributing to QS signaling" |
| Keywords: | "Bacterial Proteins/*metabolism Endopeptidases/*metabolism Gene Expression Regulation, Bacterial Gram-Positive Bacteria/metabolism Neprilysin/metabolism Pheromones/*metabolism Quorum Sensing/*physiology Signal Transduction/genetics/physiology Streptococcus;" |
| Notes: | "MedlinePerez Morales, Tiara G Ratia, Kiira Wang, Duo-Sheng Gogos, Artemis Bloem, Laura Driver, Tom G Federle, Michael J eng R01 AI091779/AI/NIAID NIH HHS/ R01 AI125452/AI/NIAID NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't 2017/12/06 J Biol Chem. 2018 Jan 19; 293(3):931-940. doi: 10.1074/jbc.M117.810994. Epub 2017 Dec 4" |
