Quorum sensing is a signal-based communication system in bacteria. It is an attractive target because it regulates the production of virulence factors in Pseudomonas aeruginosa . As a result, interference with quorum sensing could result in inhibition of virulence of Pseudomonas aeruginosa with the merit of lack of selective pressure on growth that leads to development of resistance. This study investigated the anti-quorum sensing and anti-virulence activities of febuxostat in Pseudomonas aeruginosa PAO1 strain. At 1/8 MIC of febuxostat, the production of the quorum-sensing regulated violacein pigment of Chromobacterium violaceum CV026 was significantly reduced. Moreover, it markedly reduced pyocyanin, hemolysin, protease and elastase production. Significant inhibitory activities were also found against biofilm, swimming, twitching and swarming motilities. Molecular docking showed the ability of febuxostat to inhibit quorum sensing by competing with the autoinducers to bind with LasR and RhlR receptors. Febuxostat could bind to both receptors by hydrogen bonding and hydrophobic interaction. From the Molecular docking scores, febuxostat is a very promising quorum sensing inhibitor. Febuxostat could also significantly decrease the level of expression of all QS genes LasI, LasR, RhlI, RhlR, PqsA and PqsR that regulate the production of virulene factors as confirmed by qRT-PCR.
Van Delden, C. and Iglewski, B.H. (1998) Cell-to-Cell Signaling and Pseudomonas aeruginosa Infections. Emerging Infectious Diseases, 4, 551-560.
Bjarnsholt, T., Jensen, P.Ø., Fiandaca, M.J., et al. (2009) Pseudomonas aeruginosa Biofilms in the Respira-tory Tract of Cystic Fibrosis Patients. Pediatric Pulmonology, 44, 547-558. https://doi.org/10.1002/ppul.21011
Kennedy, P., Brammah, S. and Wills, E. (2010) Burns, Biofilm and a New Appraisal of Burn Wound Sepsis. Burns, 36, 49-56. https://doi.org/10.1016/j.burns.2009.02.017
Davies, D. (2003) Understanding Biofilm Resistance to Antibacterial Agents. Nature Reviews Drug Discovery, 2, 114-122. https://doi.org/10.1038/nrd1008
Davies, D.G., Parsek, M.R., Pearson, J.P., et al. (1998) The Involvement of Cell-to-Cell Signals in the Development of a Bacterial Biofilm. Science, 280, 295-298. https://doi.org/10.1126/science.280.5361.295
Pesci, E.C., Pearson, J.P., Seed, P.C., et al. (1997) Regulation of las and rhl Quorum sensing in Pseudomonas aeruginosa. Journal of Bacteriology, 179, 3127-3132. https://doi.org/10.1128/jb.179.10.3127-3132.1997
Venturi, V. (2006) Regulation of Quorum Sensing in Pseudomonas. FEMS Microbiology Reviews, 30, 274-291. https://doi.org/10.1111/j.1574-6976.2005.00012.x
Heeb, S., Fletcher, M.P., Chhabra, S.R., et al. (2011) Quinolones: From Antibiotics to Autoinducers. FEMS Microbiology Reviews, 35, 247-274. https://doi.org/10.1111/j.1574-6976.2010.00247.x
Lee, J., Wu, J., Deng, Y., et al. (2013) A Cell-Cell Communication Signal Integrates Quorum Sensing and Stress Response. Nature Chemical Biology, 9, 339-343. https://doi.org/10.1038/nchembio.1225
Bjarnsholt, T., Ciofu, O., Molin, S., et al. (2013) Applying Insights from Biofilm Biology to Drug Development—Can a New Approach Be Developed? Nature Reviews Drug Discovery, 12, 791-808.
Hentzer, M., Wu, H., Andersen, J.B., et al. (2003) Attenuation of Pseudomonas aeruginosa Virulence by Quorum Sensing Inhibitors. The EMBO Journal, 22, 3803-3815. https://doi.org/10.1093/emboj/cdg366
Osada, Y., Tsuchimoto, M., Fukushima, H., et al. (1993) Hypouricemic Effect of the Novel Xanthine Oxidase Inhibitor, TEI-6720, in Rodents. European Journal of Pharmacology, 241, 183-188. https://doi.org/10.1016/0014-2999(93)90201-R
Komoriya, K., Osada, Y., Hasegawa, M., et al. (1993) Hypouricemic Effect of Allopurinol and the Novel Xanthine Oxidase Inhibitor TEI-6720 in Chimpanzees. European Journal of Pharmacology, 250, 455-460. https://doi.org/10.1016/0014-2999(93)90033-E
Clinical and Laboratory Standards Institute (2012) Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically. Approval Standard CDM-A, Vol. 32.
Nalca, Y., Jänsch, L., Bredenbruch, F., et al. (2006) Quorum-Sensing Antagonistic Activities of Azithromycin in Pseudomonas aeruginosa PAO1: A Global Approach. Antimicrobial Agents and Chemotherapy, 50, 1680-1688. https://doi.org/10.1128/AAC.50.5.1680-1688.2006
Choo, J., Rukayadi, Y. and Hwang, J.K. (2006) Inhibition of Bacterial Quorum Sensing by Vanilla Extract. Letters in Applied Microbiology, 42, 637-641. https://doi.org/10.1111/j.1472-765X.2006.01928.x
Stepanović, S., Vuković, D., Hola, V., et al. (2007) Quantification of Biofilm in Microtiter Plates: Overview of Testing Conditions and Practical Recommendations for Assessment of Biofilm Production by Staphylococci. Apmis, 115, 891-899. https://doi.org/10.1111/j.1600-0463.2007.apm_630.x
Rashid, M.H. and Kornberg, A. (2000) Inorganic Polyphosphate Is Needed for Swimming, Swarming, and Twitching Motilities of Pseudomonas aeruginosa. Proceedings of the National Academy of Sciences, 97, 4885-4890. https://doi.org/10.1073/pnas.060030097
Vijayaraghavan, P. and Vincent, S.G.P. (2013) A Simple Method for the Detection of Protease Activity on Agar Plates Using Bromocresolgreen Dye. Journal of Biochemical Technology, 4, 628-630.
Ohman, D., Cryz, S. and Iglewski, B. (1980) Isolation and Characterization of Pseudomonas aeruginosa PAO Mutant That Produces Altered Elastase. Journal of Bacteriology, 142, 836-842.
Das, T. and Manefield, M. (2012) Pyocyanin Promotes Extracellular DNA Release in Pseudomonas aeruginosa. PLoS ONE, 7, e46718. https://doi.org/10.1371/journal.pone.0046718
Rossignol, G., Merieau, A., Guerillon, J., et al. (2008) Involvement of a Phospholipase C in the Hemolytic Activity of a Clinical Strain of Pseudomonas fluorescens. BMC Microbiology, 8, 189. https://doi.org/10.1186/1471-2180-8-189
Livak, K.J. and Schmittgen, T.D. (2001) Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2-ΔΔCT Method. Methods, 25, 402-408. https://doi.org/10.1006/meth.2001.1262
Bottomley, M.J., Muraglia, E., Bazzo, R., et al. (2007) Molecular Insights into Quorum Sensing in the Human Pathogen Pseudomonas aeruginosa from the Structure of the Virulence Regulator LasR Bound to Its Autoinducer. Journal of Biological Chemistry, 282, 13592-600. https://doi.org/10.1074/jbc.M700556200
Thomsen, R. and Christensen, M.H. (2006) MolDock: A New Technique for High-Accuracy Molecular Docking. Journal of Medicinal Chemistry, 49, 3315-3321. https://doi.org/10.1021/jm051197e
Lau, G.W., Ran, H., Kong, F., et al. (2004) Pseudomonas aeruginosa Pyocyanin Is Critical for Lung Infection in Mice. Infection and Immunity, 72, 4275-4278. https://doi.org/10.1128/IAI.72.7.4275-4278.2004
Zhao, T. and Liu, Y. (2010) N-Acetylcysteine Inhibit Biofilms Produced by Pseudomonas aeruginosa. BMC Microbiology, 10, 140. https://doi.org/10.1186/1471-2180-10-140
Adonizio, A.L., Downum, K., Bennett, B.C., et al. (2006) Anti-Quorum Sensing Activity of Medicinal Plants in Southern Florida. Journal of Ethnopharmacology, 105, 427-435. https://doi.org/10.1016/j.jep.2005.11.025
Galloway, W.R., Hodgkinson, J.T., Bowden, S., et al. (2012) Applications of Small Molecule Activators and Inhibitors of Quorum Sensing in Gram-Negative Bacteria. Trends in Microbiology, 20, 449-458. https://doi.org/10.1016/j.tim.2012.06.003
Abbas, H.A. and Shaldam, M.A. (2016) Glyceryl Trinitrate Is a Novel Inhibitor of Quorum Sensing in Pseudomonas aeruginosa. African Health Sciences, 16, 1109-1117. https://doi.org/10.4314/ahs.v16i4.29
Abbas, H.A., Elsherbini, A.M. and Shaldam, M.A. (2017) Repurposing Metformin as a Quorum Sensing Inhibitor in Pseudomonas aeruginosa. African Health Sciences, 17, 808-819. https://doi.org/10.4314/ahs.v17i3.24
Stauff, D.L. and Bassler, B.L. (2011) Quorum Sensing in Chromobacterium violaceum: DNA Recognition and Gene Regulation by the CviR Receptor. Journal of Bacteriology, 193, 3871-3878. https://doi.org/10.1128/JB.05125-11
Kirisits, M.J. and Parsek, M.R. (2006) Does Pseudomonas aeruginosa Use Intercellular Signalling to Build Biofilm Communities? Cellular Microbiology, 8, 1841-1849. https://doi.org/10.1111/j.1462-5822.2006.00817.x
Glessner, A., Smith, R.S., Iglewski, B.H., et al. (1999) Roles of Pseudomonas aeruginosa las and rhl Quorum-Sensing Systems in Control of Twitching Motility. Journal of Bacteriology, 181, 1623-1629.
Heydorn, A., Ersbøll, B., Kato, J., et al. (2002) Statistical Analysis of Pseudomonas aeruginosa Biofilm Development: Impact of Mutations in Genes Involved in Twitching Motility, Cell-to-Cell Signaling, and Stationary-Phase Sigma Factor Expression. Applied and Environmental Microbiology, 68, 2008-2017. https://doi.org/10.1128/AEM.68.4.2008-2017.2002
Gupta, R.K., Setia, S. and Harjai, K. (2011) Expression of Quorum Sensing and Virulence Factors Are Interlinked in Pseudomonas aeruginosa: An in Vitro Approach. American Journal of Biomedical Sciences, 3, 116-125. https://doi.org/10.5099/aj110200116