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.
Highlights
Bacteria produce chemical signals to coordinate behaviors across a population in a process termed quorum sensing (QS)
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 short hydrophobic pheromones (SHPs) pheromones, was unresponsive to the compound
Because QS systems are responsive to extracellular pheromones, there is a strong potential to harness or manipulate bacterial behavior through modulation of sensory systems through exogenous application of chemical agonists and antagonists
Summary
Bacteria produce chemical signals (pheromones) to coordinate behaviors across a population in a process termed quorum sensing (QS). 1 Recipient of Natural Products Complementary and Alternative Medicine bacterial populations This social regulation of behavior provides benefits to bacteria in a variety of ways, for instance in cooperative sharing of resources (secreted enzymes [1, 2]), in coordinating horizontal gene transfer (conjugation and natural transformation, [3, 4]), and in defending the community (biofilm development, [5]). Among species of Streptococcus, a widespread QS system is one that relies on short, linear peptides as pheromones that bind directly to a receptor family termed Rgg (named after the prototype called regulator of glucosyl transferase genes) [6]. Called ComR, is a transcriptional activator that binds to the pheromone termed XIP (comX-inducing peptide) and induces expression of a large regulon of genes associated with natural competence [13,14,15]. Activation of Rgg and Rgg is associated with biofilm development in some strains of S. pyogenes, as well as enhanced lysozyme resistance and antibiotic sensitivity [16]
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