What is Quorum Sensing?

Quorum sensing is a chemical communication mechanism used by many common bacteria to initiate group behaviors. It plays an important role in the establishment of infection by pathogens and in mediating certain symbioses.1

As quorum sensing is dependent on small-molecule signals produced by the bacteria, there is significant interest in developing chemical strategies to interfere with these signals and attenuate quorum sensing-controlled behaviors.

The Blackwell laboratory has developed several chemical tools that strongly modulate quorum sensing pathways in common Gram-negative bacteria by targeting LuxR-type receptors. A suite of the most versatile ligands (804223, 804231, 804258, 804339, 804347) are now available for research purposes; their compound names from Blackwell group publications are provided next to the products below for reference.

Advantages of Quorum Sensing Modulators

  • Amongst the most potent synthetic quorum sensing inhibitors and activators to be reported
  • Active in wild-type bacteria where many strongly modulate important quorum sensing phenotypes (motility, virulence factor production, etc.)
  • No effect on bacterial growth at standard concentrations
  • Bench stable; highly soluble in common biological media
  • 3-oxo-C12 aniline has enhanced hydrolytic stability relative to lactone tools

Representative Applications

Below is a depiction of quorum sensing where bacteria use receptors (green) to sense the signals (red) produced by nearby bacteria, allowing them to communicate the density of their population. As the concentration of signal increases with a growing population (quorum), bacteria adjust their behavior.1 Ligands from the Blackwell lab are valuable tools to modulate these receptors and thus quorum sensing-related processes. These compounds strongly inhibit or activate LasR, RhlR, and QscR from Pseudomonas aeruginosa,2–6 LuxR from Vibrio fischeri,7 TraR from Agrobacterium tumefaciens,2 the putative LuxR receptor (AbaR) from Acinetobacter baumannii,6 ExpR1/ExpR2 from Pectobacterium carotovora,9–10 and several other LuxR-type receptors from related species.12–13

Quorum Sensing Modulators

Special thanks to Professor Helen Blackwell for contributing this technology spotlight.

Materials
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References

1.
Geske GD, O?Neill JC, Blackwell HE. 2008. Expanding dialogues: from natural autoinducers to non-natural analogues that modulate quorum sensing in Gram-negative bacteria. Chem. Soc. Rev.. 37(7):1432. http://dx.doi.org/10.1039/b703021p
2.
Geske GD, O'Neill JC, Miller DM, Mattmann ME, Blackwell HE. 2007. Modulation of Bacterial Quorum Sensing with Synthetic Ligands:  Systematic Evaluation ofN-Acylated Homoserine Lactones in Multiple Species and New Insights into Their Mechanisms of Action. J. Am. Chem. Soc.. 129(44):13613-13625. http://dx.doi.org/10.1021/ja074135h
3.
Mattmann ME, Geske GD, Worzalla GA, Chandler JR, Sappington KJ, Greenberg EP, Blackwell HE. 2008. Synthetic ligands that activate and inhibit a quorum-sensing regulator in Pseudomonas aeruginosa. Bioorganic & Medicinal Chemistry Letters. 18(10):3072-3075. http://dx.doi.org/10.1016/j.bmcl.2007.11.095
4.
McInnis CE, Blackwell HE. 2011. Design, synthesis, and biological evaluation of abiotic, non-lactone modulators of LuxR-type quorum sensing. Bioorganic & Medicinal Chemistry. 19(16):4812-4819. http://dx.doi.org/10.1016/j.bmc.2011.06.072
5.
Welsh MA, Eibergen NR, Moore JD, Blackwell HE. 2015. Small Molecule Disruption of Quorum Sensing Cross-Regulation inPseudomonas aeruginosaCauses Major and Unexpected Alterations to Virulence Phenotypes. J. Am. Chem. Soc.. 137(4):1510-1519. http://dx.doi.org/10.1021/ja5110798
6.
Eibergen NR, Moore JD, Mattmann ME, Blackwell HE. 2015. Potent and Selective Modulation of the RhlR Quorum Sensing Receptor by Using Non-native Ligands: An Emerging Target for Virulence Control inPseudomonas aeruginosa. ChemBioChem. 16(16):2348-2356. http://dx.doi.org/10.1002/cbic.201500357
7.
Geske GD, O?Neill JC, Blackwell HE. 2007. N-Phenylacetanoyl-l-Homoserine Lactones Can Strongly Antagonize or Superagonize Quorum Sensing in Vibrio fischeri. ACS Chem. Biol.. 2(5):315-319. http://dx.doi.org/10.1021/cb700036x
8.
Stacy DM, Welsh MA, Rather PN, Blackwell HE. 2012. Attenuation of Quorum Sensing in the PathogenAcinetobacter baumanniiUsing Non-nativeN-Acyl Homoserine Lactones. ACS Chem. Biol.. 7(10):1719-1728. http://dx.doi.org/10.1021/cb300351x
9.
Palmer AG, Streng E, Blackwell HE. 2011. Attenuation of Virulence in Pathogenic Bacteria Using Synthetic Quorum-Sensing Modulators under Native Conditions on Plant Hosts. ACS Chem. Biol.. 6(12):1348-1356. http://dx.doi.org/10.1021/cb200298g
10.
Palmer AG, Streng E, Jewell KA, Blackwell HE. 2011. Quorum Sensing in Bacterial Species that Use Degenerate Autoinducers Can Be Tuned by Using Structurally Identical Non-native Ligands. ChemBioChem. 12(1):138-147. http://dx.doi.org/10.1002/cbic.201000551
11.
Praneenararat T, Palmer AG, Blackwell HE. 2012. Chemical methods to interrogate bacterial quorum sensing pathways. Org. Biomol. Chem.. 10(41):8189. http://dx.doi.org/10.1039/c2ob26353j
12.
Galloway WRJD, Hodgkinson JT, Bowden SD, Welch M, Spring DR. 2011. Quorum Sensing in Gram-Negative Bacteria: Small-Molecule Modulation of AHL and AI-2 Quorum Sensing Pathways. Chem. Rev.. 111(1):28-67. http://dx.doi.org/10.1021/cr100109t

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