posted on 2018-06-19, 00:00authored byTiara G. Morales, Kiira Ratia, Duo-Sheng Wang, Artemis Gogos, Tom G. Driver, Michael J. Federle
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 metallo-endopeptidase 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.
Funding
Primary funding provided by NIH grants AI091779 and AI125452 and the Chicago Biomedical Consortium with support from the Searle Funds at The Chicago Community Trust. T.P.M. is a grantee of the Natural Products Complementary and Alternative Medicine training grant (NIH-5T32AT007533).
History
Publisher Statement
Copyright @ American Society for Biochemistry and Molecular Biology
Citation
Morales, T. G. P., Ratia, K., Wang, D. S., Gogos, A., Driver, T. G. and Federle, M. J. A novel chemical inducer of Streptococcus quorum sensing acts by inhibiting the pheromone-degrading endopeptidase PepO. Journal of Biological Chemistry. 2018. 293(3): 931-940. 10.1074/jbc.M117.810994.
Publisher
American Society for Biochemistry and Molecular Biology