Many bacteria grow on surfaces forming biofilms. In this structure, they are well protected and often high dosages of antibiotics cannot clear infectious biofilms. The formation and stabilization of biofilms are mediated by diffusible autoinducers (e.g. N-acyl homoserine lactones, small peptides, furanosyl borate diester). Metabolites interfering with this process have been identified in plants, animals and microbes, and synthetic analogues are known. Additionally, this seems to be not the only way to control biofilms. Enzymes capable of cleaving essential components of the biofilm matrix, e.g. polysaccharides or extracellular DNA, and thus weakening the biofilm architecture have been identified. Bacteria also have mechanisms to dissolve their biofilms and return to planktonic lifestyle. Only a few compounds responsible for the signalling of these processes are known, but they may open a completely novel line of biofilm control. All these approaches lead to the destruction of the biofilm but not the killing of the pathogens. Therefore, a combination of biofilm-destroying compounds and antibiotics to handle biofilm infections is proposed. In this article, different approaches to combine biofilm-controlling compounds and antibiotics to fight biofilm infections are discussed, as well as the balance between biofilm formation and virulence.
References
[1]
Singh, P.K.; Schaefer, A.L.; Parsek, M.R.; Moninger, T.O.; Welsh, M.J.; Greenberg, E.P. Quorum-sensing signals indicate that cystic fibrosis lungs are infected with bacterial biofilms. Nature？2000, 407, 762–764, doi:10.1038/35037627. 11048725
[2]
Hall-Stoodley, L.; Hu, F.Z.; Gieseke, A.; Nistico, L.; Nguyen, D.; Hayes, J.; Forbes, M.; Greenberg, D.P.; Dice, B.; Burrows, A.; Wackym, P.A.; Stoodley, P.; Post, J.C.; Ehrlich, G.D.; Kerschner, J.E. Direct detection of bacterial biofilms on the middle-ear mucosa of children with chronic otitis media. JAMA？2006, 296, 202–211, doi:10.1001/jama.296.2.202. 16835426
[3]
Carron, M.A.; Tran, V.R.; Sugawa, C.; Coticchia, J.M. Identification of Helicobacter pylori biofilms in human gastric mucosa. J. Gastrointest. Surg.？2006, 10, 712–717, doi:10.1016/j.gassur.2005.10.019. 16713544
[4]
Hall-Stoodley, L.; Costerton, J.W.; Stoodley, P. Bacterial biofilms: From the natural environment to infectious diseases. Nat. Rev. Microbiol.？2004, 2, 95–108, doi:10.1038/nrmicro821. 15040259
[5]
Leone, M.; Dillon, L.R. Catheter outcomes in home infusion. J. Infus. Nurs.？2008, 31, 84–91, doi:10.1097/01.NAN.0000313655.65410.4e. 18344768
Stewart, P.S.; Costerton, J.W. Antibiotic resistance of bacteria in biofilms. Lancet？2001, 358, 135–138, doi:10.1016/S0140-6736(01)05321-1. 11463434
[8]
Joly, V.; Pangon, B.; Vallois, J.M.; Abel, L.; Brion, N.; Bure, A.; Chau, N.P.; Contrepois, A.; Carbon, C. Value of antibiotic levels in serum and cardiac vegetations for predicting antibacterial effect of ceftriaxone in experimental Escherichia coli endocarditis. Antimicrob. Agents Chemother.？1987, 31, 1632–1639. 3324957
[9]
Schuster, M.; Lostroh, C.P.; Ogi, T.; Greenberg, E.P. Identification, timing, and signal specificity of Pseudomonas aeruginosa quorum-controlled genes: A transcriptome analysis. J. Bacteriol.？2003, 185, 2066–2079, doi:10.1128/JB.185.7.2066-2079.2003. 12644476
[10]
Mah, T.-F.; Pitts, B.; Pellock, B.; Walker, G.C.; Stewart, P.S.; O’Toole, G.A. A genetic basis for Pseudomonas aeruginosa biofilm antibiotic resistance. Nature？2003, 426, 306–310. 14628055
[11]
Butler, M.T.; Wang, Q.; Harshey, R.M. Cell density and mobility protect swarming bacteria against antibiotics. Proc. Natl. Acad. Sci. USA？2010, 107, 3776–3781, doi:10.1073/pnas.0910934107. 20133590
[12]
Schauder, S.; Bassler, B.L. The languages of bacteria. Genes Dev.？2001, 15, 1468–1480, doi:10.1101/gad.899601. 11410527
Shrout, J.D.; Chopp, D.L.; Just, C.L.; Hentzer, M.; Givskov, M.; Parsek, M.R. The impact of quorum sensing and swarming motility on Pseudomonas aeruginosa biofilm formation is nutritionally conditional. Mol. Microbiol.？2006, 62, 1264–1277, doi:10.1111/j.1365-2958.2006.05421.x. 17059568
[15]
Duan, K.; Surette, M.G. Environmental regulation of Pseudomonas aeruginosa PAO1 Las and Rhl quorum-sensing systems. J. Bacteriol.？2007, 189, 4827–4836, doi:10.1128/JB.00043-07. 17449617
[16]
Bollinger, N.; Hassett, D.J.; Iglewski, B.H.; Costerton, J.W.; McDermott, T.R. Gene expression in Pseudomonas aeruginosa: Evidence of iron override effects on quorum sensing and biofilm-specific gene regulation. J. Bacteriol.？2001, 183, 1990–1996, doi:10.1128/JB.183.6.1990-1996.2001. 11222597
[17]
Wagner, V.E.; Gillis, R.J.; Iglewski, B.H. Transcriptome analysis of quorum-sensing regulation and virulence factor expression in Pseudomonas aeruginosa. Vaccine？2004, 22 (Suppl.1), S15–S20, doi:10.1016/j.vaccine.2004.08.011. 15576196
[18]
Abraham, W.-R. Controlling Gram-negative pathogenic bacteria by interfering with their biofilm formation. Drug Design Rev. Online？2005, 2, 13–33, doi:10.2174/1567269053390257.
[19]
Chen, X.; Schauder, S.; Potier, N.; Van Dorsselaer, A.; Pelczer, I.; Bassler, B.L.; Hughson, F.M. Structural identification of a bacterial quorum-sensing signal containing boron. Nature？2002, 415, 545–549, doi:10.1038/415545a. 11823863
[20]
Miller, S.T.; Xavier, K.B.; Campagna, S.R.; Taga, M.E.; Semmelhack, M.F.; Bassler, B.L.; Hughson, F.M. Salmonella typhimurium recognizes a chemically distinct form of the bacterial quorum-sensing signal AI-2. Mol. Cell？2004, 15, 677–687, doi:10.1016/j.molcel.2004.07.020. 15350213
[21]
Xavier, K.B.; Miller, S.T.; Lu, W.; Kim, J.H.; Rabinowitz, J.; Pelczer, I.; Semmelhack, M.F.; Bassler, B.L. Phosphorylation and processing of the quorum-sensing molecule autoinducer-2 in enteric bacteria. Chem. Biol.？2007, 2, 128–136.
[22]
Taga, M.E.; Semmelhack, J.L.; Bassler, B.L. The LuxS-dependent autoinducer AI-2 controls the expression of an ABC transporter that functions in AI-2 uptake in Salmonella typhimurium. Mol. Microbiol.？2001, 42, 777–798. 11722742
[23]
Taga, M.E.; Miller, S.T.; Bassler, B.L. Lsr-mediated transport and processing of AI-2 in Salmonella typhimurium. Mol. Microbiol.？2003, 50, 1411–1427, doi:10.1046/j.1365-2958.2003.03781.x. 14622426
[24]
Rezzonico, F.; Duffy, B. Lack of genomic evidence of AI-2 receptors suggests a non-quorum sensing role for luxS in most bacteria. BMC Microbiology？2008, 8, 154–172, doi:10.1186/1471-2180-8-154. 18803868
[25]
Doherty, N.; Holden, M.T.; Qazi, S.N.; Williams, P.; Winzer, K. Functional analysis of luxS in Staphylococcus aureus reveals a role in metabolism but not quorum sensing. J. Bacteriol.？2006, 188, 2885–2897, doi:10.1128/JB.188.8.2885-2897.2006. 16585750
[26]
Lyon, G.J.; Novick, R.P. Peptide signaling in Staphylococcus aureus and other Gram-positive bacteria. Peptides？2004, 25, 1389–1403, doi:10.1016/j.peptides.2003.11.026. 15374643
[27]
McDowell, P.; Affas, Z.; Reynolds, C.; Holden, M.T.G.; Wood, S.J.; Saint, S.; Cockayne, A.; Hill, P.J.; Dodd, C.E.R.; Bycroft, B.W.; Chan, W.C.; Williams, P. Structure, activity and evolution of the group I thiolactone peptide quorum-sensing system of Staphylococcus aureus. Mol. Microbiol.？2001, 41, 503–512, doi:10.1046/j.1365-2958.2001.02539.x. 11489134
[28]
Abraham, W.-R. Controlling the biofilm formation of Gram-positive pathogenic bacteria. Curr. Med. Chem.？2006, 13, 1509–1524, doi:10.2174/092986706777442039. 16787201
[29]
Otto, M.; Süssmuth, R.; Jung, G.; G？tz, F. Structure of the pheromone peptide of the Staphylococcus epidermidis agr system. FEBS Lett.？1998, 424, 89–94, doi:10.1016/S0014-5793(98)00145-8. 9537521
[30]
Ji, G.; Beavis, R.; Novick, R.P. Bacterial interference caused by autoinducing peptide variants. Science？1997, 276, 2027–2030, doi:10.1126/science.276.5321.2027. 9197262
[31]
Keller, L.; Surette, M.G. Communication in bacteria: An ecological and evolutionary perspective. Nat. Rev. Microbiol.？2006, 4, 249–258, doi:10.1038/nrmicro1383. 16501584
[32]
Bansal, T.; Jesudhasan, P.; Pillai, S.; Wood, T.K.; Jayaraman, A. Temporal regulation of enterohemorrhagic Escherichia coli virulence mediated by autoinducer-2. Appl. Microbiol. Biotechnol.？2008, 78, 811–819, doi:10.1007/s00253-008-1359-8. 18256823
[33]
Riedel, K.; Hentzer, M.; Geisenberger, O.; Huber, B.; Steidle, A.; Wu, H.; H？iby, N.; Givskov, M.; Molin, S.; Eberl, L. N-Acylhomoserine-lactone-mediated communication between Pseudomonas aeruginosa and Burkholderia cepacia in mixed biofilms. Microbiology？2001, 147, 3249–3262. 11739757
[34]
Burm？lle, M.; Webb, J.S.; Rao, D.; Hansen, L.H.; S？rensen, S.J.; Kjelleberg, S. Enhanced biofilm formation and increased resistance to antimicrobial agents and bacterial invasion are caused by synergistic interactions in multispecies biofilms. Appl. Environm. Microbiol.？2006, 72, 3916–3923, doi:10.1128/AEM.03022-05.
[35]
Duan, K.; Dammel, C.; Stein, J.; Rabin, H.; Surette, M.G. Modulation of Pseudomonas aeruginosa gene expression by host microflora through interspecies communication. Mol. Microbiol.？2003, 50, 1477–1491, doi:10.1046/j.1365-2958.2003.03803.x. 14651632
[36]
Kaufmann, G.F.; Sartorio, R.; Lee, S.-H.; Rogers, C.J.; Meijler, M.M.; Moss, J.A.; Clapham, B.; Brogan, A.P.; Dickerson, T.J.; Janda, K.D. Revisiting quorum sensing: Discovery of additional chemical and biological functions for 3-oxo-N-acylhomoserine lactones. Proc. Natl. Acad. Sci. USA？2005, 102, 309–314, doi:10.1073/pnas.0408639102. 15623555
[37]
de Nys, R.; Wright, A.D.; K？nig, G.M.; Sticher, O. New halogenated furanones from the marine red alga Delisea pulchra (cf.fimbriata). Tetrahedron？1993, 49, 11213–11220, doi:10.1016/S0040-4020(01)81808-1.
[38]
Manefield, M.; de Nys, R.; Kumar, N.; Read, R.; Givskov, M.; Steinberg, P.; Kjelleberg, S. Evidence that halogenated furanones from Delisea pulchra inhibit acylated homoserine lactone (AHL)-mediated gene expression by displacing the AHL signal from its receptor protein. Microbiol.？1999, 145, 283–291, doi:10.1099/13500872-145-2-283.
[39]
Hjelmgaard, T.; Persson, T.; Rasmussen, T.B.; Givskov, M.; Nielsen, J. Synthesis of furanone-based natural product analogues with quorum sensing antagonist activity. Bioorg. Med. Chem.？2003, 11, 3261–3271, doi:10.1016/S0968-0896(03)00295-5. 12837536
[40]
Estephane, J.; Dauvergne, J.; Soulère, L.; Reverchon, S.; Queneau, Y.; Doutheu, A. N-Acyl-3-amino-5H-furanone derivatives as new inhibitors of LuxR-dependent quorum sensing: Synthesis, biological evaluation and binding mode study. Bioorg. Med. Chem. Lett.？2008, 18, 4321–4324. 18625553
[41]
Kim, C.; Kim, J.; Park, H.Y.; Park, H.J.; Lee, J.H.; Kim, C.K.; Yoon, J. Furanone derivatives as quorum-sensing antagonists of Pseudomonas aeruginosa. Appl. Microbiol. Biotechnol.？2008, 80, 37–47, doi:10.1007/s00253-008-1474-6. 18566810
[42]
Ren, D.; Sims, J.J.; Wood, T.K. Inhibition of biofilm formation and swarming of Escherichia coli by (5Z)-4-bromo-5-(bromomethylene)-3-butyl-2(5H)-furanone. Environ. Microbiol.？2001, 3, 731–736, doi:10.1046/j.1462-2920.2001.00249.x. 11846763
[43]
Wu, H.; Song, Z.; Givskov, M.; Doring, G.; Worlitzsch, D.; Mathee, K.; Rygaard, J.; H？iby, N. Pseudomonas aeruginosa mutations in lasI and rhlI quorum sensing systems result in milder chronic lung infection. Microbiology？2001, 147, 1105–1113. 11320114
[44]
Wu, H.; Song, Z.; Hentzer, M.; Andersen, J.B.; Molin, S.; Givskov, M.; H？iby, N. Synthetic furanones inhibit quorum-sensing and enhance bacterial clearance in Pseudomonas aeruginosa lung infection in mice. J. Antimicrob. Chemother.？2004, 53, 1054–1061, doi:10.1093/jac/dkh223. 15117922
[45]
Harjai, K.; Kumar, R.; Singh, S. Garlic blocks quorum sensing and attenuates the virulence of Pseudomonas aeruginosa. FEMS Immunol. Med. Microbiol.？2010, 58, 161–168, doi:10.1111/j.1574-695X.2009.00614.x. 19878318
[46]
Smyth, A.R.; Cifelli, P.M.; Ortori, C.A.; Righetti, K.; Lewis, S.; Erskine, P.; Holland, E.D.; Givskov, M.; Williams, P.; Cámara, M.; Barrett, D.A.; Knox, A. Garlic as an inhibitor of Pseudomonas aeruginosa quorum sensing in cystic fibrosis--a pilot randomized controlled trial. Pediatr. Pulmonol.？2010, 45, 356–362. 20306535
[47]
Rudrappa, T.; Bais, H.P. Curcumin, a known phenolic from Curcuma longa, attenuates the virulence of Pseudomonas aeruginosa PAO1 in whole plant and animal pathogenicity models. J. Agric. Food Chem.？2008, 56, 1955–1962, doi:10.1021/jf072591j. 18284200
[48]
Vikram, A.; Jayaprakasha, G.K.; Jesudhasan, P.R.; Pillai, S.D.; Patil, B.S. Suppression of bacterial cell-cell signalling, biofilm formation and type III secretion system by citrus flavonoids. J. Appl. Microbiol.？2010, doi:10.1111/j.1365-2672.2010.04677.x.
[49]
Reverchon, S.; Chantegrel, B.; Deshayes, C.; Doutheau, A.; Cotte-Pattat, N. New synthetic analogues of N-acyl homoserine lactones as agonists or antagonists of transcriptional regulators involved in bacterial quorum sensing. Bioorg. Med. Chem. Lett.？2002, 12, 1153–1157, doi:10.1016/S0960-894X(02)00124-5. 11934577
[50]
Müh, U.; Schuster, M.; Heim, R.; Singh, A.; Olson, E.R.; Greenberg, E.P. Novel Pseudomonas aeruginosa quorum-sensing inhibitors identified in an ultra-high-throughput screen. Antimicrob. Agents Chemother.？2006, 50, 3674–3679, doi:10.1128/AAC.00665-06. 16966394
[51]
Smith, K.M.; Bu, Y.; Suga, H. Library screening for synthetic agonists and antagonists of a Pseudomonas aeruginosa autoinducer. Chem. Biol.？2003, 10, 563–571, doi:10.1016/S1074-5521(03)00107-8. 12837389
[52]
Smith, K.M.; Bu, Y.; Suga, H. Induction and inhibition of Pseudomonas aeruginosa quorum sensing by synthetic autoinducer analogs. Chem. Biol.？2003, 10, 81–89, doi:10.1016/S1074-5521(03)00002-4. 12573701
[53]
Mattmann, M.E.; Geske, G.D.; Worzalla, G.A.; Chandler, J.R.; Sappington, K.J.; Greenberg, E.P.; Blackwell, H.E. Synthetic ligands that activate and inhibit a quorum-sensing regulator in Pseudomonas aeruginosa. Bioorg. Med. Chem. Lett.？2008, 18, 3072–3075. 18083553
[54]
Geske, G.D.; O'Neill, J.C.; Blackwell, H.E. N-phenylacetanoyl-L-homoserine lactones can strongly antagonize or superagonize quorum sensing in Vibrio fischeri. ACS Chem. Biol.？2007, 2, 315–219, doi:10.1021/cb700036x. 17480049
[55]
Geske, G.D.; Wezeman, R.J.; Siegel, A.P.; Blackwell, H.E. Small molecule inhibitors of bacterial quorum sensing and biofilm formation. J. Am. Chem. Soc.？2005, 127, 12762–12763. 16159245
[56]
Geske, G.D.; O'Neill, J.C.; Miller, D.M.; Mattmann, M.E.; Blackwell, H.E. Modulation of bacterial quorum sensing with synthetic ligands: systematic evaluation of N-acylated homoserine lactones in multiple species and new insights into their mechanisms of action. J. Am. Chem. Soc.？2007, 129, 13613–13625. 17927181
[57]
Forenza, S.; Minale, L.; Riccio, R.; Fattorusso, E. New bromo-pyrrole derivatives from the sponge. Agelas oroides. J. Chem. Soc. D？1971, 1129–1130, doi:10.1039/c29710001129.
Richards, J.J.; Reyes, S.; Stowe, S.D.; Tucker, A.T.; Ballard, T.E.; Mathies, L.D.; Cavanagh, J.; Melander, C. Amide isosteres of oroidin: assessment of antibiofilm activity and C. elegans toxicity. J. Med. Chem.？2009, 52, 4582–4585. 19719234
[60]
Ballard, T.E.; Richards, J.J.; Aquino, A.; Reed, C.S.; Melander, C. Antibiofilm activity of a diverse oroidin library generated through reductive acylation. J. Org. Chem.？2009, 74, 1755–1758, doi:10.1021/jo802260t. 19132935
[61]
Shen, G.; Rajan, R.; Zhu, J.; Bell, C.E.; Pei, D. Design and synthesis of substrate and intermediate analogue inhibitors of S-ribosylhomocysteinase. J. Med. Chem.？2006, 49, 3003–3011, doi:10.1021/jm060047g. 16686542
[62]
Ni, N.; Chou, H.-T.; Wang, J.; Li, M.; Lu, C.-D.; Tai, P.C.; Wang, B. Identification of boronic acids as antagonists of bacterial quorum sensing in Vibrio harveyi. Biochem. Biophys. Res. Comm.？2008, 369, 590–594, doi:10.1016/j.bbrc.2008.02.061.
[63]
Mayville, P.; Ji, G.; Beavis, R.; Yang, H.; Goger, M.; Novick, R.P.; Muir, T.W. Structure-activity analysis of synthetic autoinducing thiolactone peptides from Staphylococcus aureus responsible for virulence. Proc. Natl. Acad. Sci. USA？1999, 96, 1218–1223, doi:10.1073/pnas.96.4.1218. 9990004
[64]
Wright III, J.S.; Lyon, G.J.; George, E.A.; Muir, T.W.; Novick, R.P. Hydrophobic interactions drive ligand-receptor recognition for activation and inhibition of staphylococcal quorum sensing. Proc. Nat. Acad. Sci. USA？2004, 101, 16168–16173, doi:10.1073/pnas.0404039101. 15528279
[65]
McDowell, P.; Affas, Z.; Reynolds, C.; Holden, M.T.G.; Wood, S.J.; Saint, S.; Cockayne, A.; Hill, P.J.; Dodd, C.E.R.; Bycroft, B.W.; Chan, W.C.; Williams, P. Structure, activity and evolution of the group I thiolactone peptide quorum-sensing system of Staphylococcus aureus. Mol. Microbiol.？2001, 41, 503–512. 11489134
[66]
Lyon, G.J.; Wright, J.S.; Muir, T.W.; Novick, R.P. Key determinants of receptor activation in the agr autoinducing peptides of Staphylococcus aureus. Biochemistry？2002, 41, 10095–10104, doi:10.1021/bi026049u. 12146974
[67]
Harraghy, N.; Kerdudou, S.; Herrmann, M. Quorum-sensing systems in staphylococci as therapeutic targets. Anal. Bioanal. Chem.？2007, 387, 437–444, doi:10.1007/s00216-006-0860-0. 17072597
[68]
Kjelleberg, S.; Molin, S. Is there a role for quorum sensing signals in bacterial biofilms? Curr. Opinion Microbiol.？2002, 5, 254–258, doi:10.1016/S1369-5274(02)00325-9.
[69]
Dow, M. Diversification of the function of cell-to-cell signaling in regulation of virulence within plant pathogenic xanthomonads. Sci. Signal.？2008, 1, pe23, doi:10.1126/stke.121pe23. 18506032
[70]
Looney, W.J. Role of Stenotrophomonas maltophilia in hospital-acquired infection. Br. J. Biomed. Sci.？2005, 62, 145–154. 16196464
[71]
Huang, T.P.; Wong, A.C. Extracellular fatty acids facilitate flagella-independent translocation by Stenotrophomonas maltophilia. Res. Microbiol.？2007, 158, 702–711, doi:10.1016/j.resmic.2007.09.002. 18054205
[72]
Ryan, R.P.; Fouhy, Y.; Garcia, B.F.; Watt, S.A.; Niehaus, K.; Yang, L.; Tolker-Nielsen, T.; Dow, J.M. Interspecies signalling via the Stenotrophomonas maltophilia diffusible signal factor influences biofilm formation and polymyxin tolerance in Pseudomonas aeruginosa. Mol. Microbiol.？2008, 68, 75–86, doi:10.1111/j.1365-2958.2008.06132.x. 18312265
[73]
Inoue, T.; Shingaki, R.; Fukui, K. Inhibition of swarming motility of Pseudomonas aeruginosa by branched-chain fatty acids. FEMS Microbiol. Lett.？2008, 281, 81–86, doi:10.1111/j.1574-6968.2008.01089.x. 18318842
[74]
Boon, C.; Deng, Y.; Wang, L.-H.; He, Y.; Xu, J.-L.; Fan, Y.; Pan, S.Q.; Zhang, L.-H. A novel DSF-like signal from Burkholderia cenocepacia interferes with Candida albicans morphological transition. ISME J.？2008, 2, 27–36, doi:10.1038/ismej.2007.76. 18049456
[75]
Snider, J. Molecule that induces biofilm dispersion discovered. JADA？2006, 137, 1643–1646. 17138708
[76]
Davies, D.G.; Marques, C.N.H. A fatty acid messenger is responsible for inducing dispersion in microbial biofilms. J. Bacteriol.？2009, 191, 1393–1403, doi:10.1128/JB.01214-08. 19074399
[77]
Romeo, T. When the party is over: A signal for dispersal of Pseudomonas aeruginosa biofilms. J. Bacteriol.？2006, 188, 7325–7327, doi:10.1128/JB.01317-06. 17050919
[78]
Schlag, S.; Nerz, C.; Birkenstock, T.A.; Altenberend, F.; G？tz, F. Inhibition of Staphylococcal biofilm formation by nitrite. J. Bacteriol.？2007, 189, 7911–7919, doi:10.1128/JB.00598-07. 17720780
Thormann, K.M.; Duttler, S.; Saville, R.M.; Hyodo, M.; Shukla, S.; Hayakawa, Y.; Spormann, A.M. Control of formation and cellular detachment from Shewanella oneidensis MR-1 biofilms by cyclic di-GMP. J. Bacteriol.？2006, 188, 2681–2691, doi:10.1128/JB.188.7.2681-2691.2006. 16547056
[82]
Tamayo, R.; Pratt, J.T.; Camilli, A. Roles of cyclic diguanylate in the regulation of bacterial pathogenesis. Annu. Rev. Microbiol.？2007, 61, 131–148, doi:10.1146/annurev.micro.61.080706.093426. 17480182
[83]
Ryan, R.P.; Fouhy, Y.; Lucey, J.F.; Dow, J.M. Cyclic di-GMP signaling in bacteria: Recent advances and new puzzles. J. Bacteriol.？2006, 188, 8327–8334, doi:10.1128/JB.01079-06. 17028282
[84]
Jenal, U.; Malone, J. Mechanisms of cyclic-di-GMP signaling in bacteria. Annu. Rev. Genet.？2006, 40, 385–407, doi:10.1146/annurev.genet.40.110405.090423. 16895465
[85]
Whitchurch, C.B.; Tolker-Nielsen, T.; Ragas, P.C.; Mattick, J.S. Extracellular DNA required for bacterial biofilm formation. Science？2002, 295, 1487–1487, doi:10.1126/science.295.5559.1487. 11859186
[86]
Qin, Z.; Ou, Y.; Yang, L.; Zhu, Y.; Tolker-Nielsen, T.; Molin, S.; Qu, D. Role of autolysin-mediated DNA release in biofilm formation of Staphylococcus epidermidis. Microbiology.？2007, 153, 2083–2092, doi:10.1099/mic.0.2007/006031-0. 17600053
[87]
Izano, E.A.; Amarante, M.A.; Kher, W.B.; Kaplan, J.B. Differential roles of poly-N-acetylglucosamine surface polysaccharide and extracellular DNA in Staphylococcus aureus and Staphylococcus epidermidis biofilms. Appl. Environm. Microbiol.？2008, 74, 470–476, doi:10.1128/AEM.02073-07.
[88]
Davies, D.G.; Marques, C.N.; Amari, D.T.; Hong, B.Y.; Mavor, J.L. Characterization of induction of biofilm dispersion by cis-2-decenoic acid. ASM Biofilms 2009, Cancun, Mexico, Book of abstracts？2009, 22.
[89]
Yahr, T.L.; Wolfgang, M.C. Transcriptional regulation of the Pseudomonas aeruginosa type III secretion system. Mol. Microbiol.？2006, 62, 631–640, doi:10.1111/j.1365-2958.2006.05412.x. 16995895
[90]
von Gotz, F.; H？ussler, S.; Jordan, D.; Saravanamuthu, S.S.; Wehmh？ner, D.; Strüssmann, A.; Lauber, J.; Attree, I.; Buer, J.; Tümmler, B.; Steinmetz, I. Expression analysis of a highly adherent and cytotoxic small colony variant of Pseudomonas aeruginosa isolated from a lung of a patient with cystic fibrosis. J. Bacteriol.？2004, 186, 3837–3847. 15175297
[91]
Mikkelsen, H.; Bond, N.J.; Skindersoe, M.E.; Givskov, M.; Lilley, K.S.; Welch, M. Biofilms and type III secretion are not mutually exclusive in Pseudomonas aeruginosa. Microbiology？2009, 155, 687–698, doi:10.1099/mic.0.025551-0. 19246740
[92]
Tamber, S.; Cheung, A.L. SarZ promotes the expression of virulence factors and represses biofilm formation by modulating SarA and agr in Staphylococcus aureus. Infect. Immun.？2009, 77, 419–428, doi:10.1128/IAI.00859-08. 18955469
[93]
O’Connell, H.A.; Kottkamp, G.S.; Eppelbaum, J.L.; Stubblefield, B.A.; Gilbert, S.E.; Gilbert, E.S. Influences of biofilm structure and antibiotic resistance mechanisms on indirect pathogenicity in a model polymicrobial biofilm. Appl. Environ. Microbiol.？2006, 72, 5013–5019, doi:10.1128/AEM.02474-05. 16820500
[94]
Bjarnsholt, T.; Jensen, P.O.; Burmolle, M.; Hentzer, M.; Haagensen, J.A.J.; Hougen, H.P.; Calum, H.; Madsen, K.G.; Moser, C.; Molin, S.; Hoiby, N.; Givskov, M. Pseudomonas aeruginosa tolerance to tobramycin, hydrogen peroxide and polymorphonuclear leukocytes is quorum-sensing dependent. Microbiology？2005, 151, 373–383, doi:10.1099/mic.0.27463-0. 15699188
[95]
Hentzer, M.; Wu, H.; Andersen, J.B.; Riedel, K.; Rasmussen, T.B.; Bagge, N.; Kumar, N.; Schembri, M.A.; Song, Z.; Kristoffersen, P.; Manefield, M.; Costerton, J.W.; Molin, S.; Eberl, L.; Steinberg, P.; Kjelleberg, S.; H？iby, N.; Givskov, M. Attenuation of Pseudomonas aeruginosa virulence by quorum sensing inhibitors. EMBO J.？2003, 22, 3803–3815. 12881415
[96]
Rasmussen, T.B.; Bjarnsholt, T.; Phipps, R.K.; Christensen, K.B.; Jensen, P.O.; Andersen, J.B.; Koch, B.; Larsen, T.O.; Hentzer, M.; Eberl, L.; Hoiby, N.; Givskov, M. Identity and effects of quorum-sensing inhibitors produced by Penicillium species. Microbiol.？2005, 151, 1325–1340, doi:10.1099/mic.0.27715-0.
Garo, E.; Eldridge, G.R.; Goering, M.G.; Pulcini, E.D.; Hamilton, M.A.; Costerton, J.W.; James, G.A. Asiatic acid and corosolic acid enhance the susceptibility of Pseudomonas aeruginosa biofilms to tobramycin. Antimicrob. Agents Chemother.？2007, 51, 1813–1817, doi:10.1128/AAC.01037-06. 17353241
[99]
Zeng, Z.; Qian, L.; Cao, L.; Tan, H.; Huang, Y.; Xue, X.; Shen, Y.; Zhou, S. Virtual screening for novel quorum sensing inhibitors to eradicate biofilm formation of Pseudomonas aeruginosa. Appl. Microbiol. Biotechnol.？2008, 79, 119–126, doi:10.1007/s00253-008-1406-5. 18330563
[100]
Barraud, N.; Hassett, D.J.; Hwang, S.-H.; Rice, S.A.; Kjelleberg, S.; Webb, J.S. Involvement of nitric oxide in biofilm dispersal of Pseudomonas aeruginosa. J. Bacteriol.？2006, 188, 7344–7353, doi:10.1128/JB.00779-06. 17050922
[101]
Rogers, S.A.; Krayer, M.; Lindsey, J.S.; Melander, C. Tandem dispersion and killing of bacteria from a biofilm. Org. Biomol. Chem.？2009, 7, 603–606, doi:10.1039/b817923a. 19156328
[102]
Rogers, S.A.; Huigens, R.W., III.; Cavanagh, J.; Melander, C. Synergistic effects between conventional antibiotics and 2-aminoimidazole-derived antibiofilm agents. Antimicrob. Agents Chemother.？2010. [Epub ahead of print].
[103]
Donelli, G.; Francolini, I.; Romoli, D.; Guaglianone, E.; Piozzi, A.; Ragunath, C.; Kaplan, J.B. Synergistic activity of dispersin B and cefamandole nafate in inhibition of staphylococcal biofilm growth in polyurethanes. Antimicrob. Agents Chemother.？2007, 51, 2733–2740. 17548491
[104]
Geske, G.D.; O’Neill, J.C.; Blackwell, H.E. N-(phenylacetanoyl)-l-homoserine lactones can strongly antagonize or superagonize quorum sensing in Vibrio fischeri. ACS Chem. Biol.？2007, 2, 315–319, doi:10.1021/cb700036x. 17480049
[105]
de Kievit, T.R. Minireview: Quorum sensing in Pseudomonas aeruginosa biofilms. Env. Microbiol.？2009, 11, 279–288, doi:10.1111/j.1462-2920.2008.01792.x.
[106]
Kay, E.; Humair, B.; Denervaud, V.; Riedel, K.; Spahr, S.; Eberl, L.; Valverde, C.; Haas, D. Two GacA-dependent small RNAs modulate the quorum-sensing response in Pseudomonas aeruginosa. J. Bacteriol.？2006, 188, 6026–6033. 16885472
