Michael Givskov

CV

English CV 

Aktuel forskning

Research grants obtained last 10 years.

(As principal investigator (PI) and partner)

• Involvement of cell-cell communication in the pathogenesis of chronic Pseudomonas aeruginosa lung infection in cystic fibrosis. Supported by SSVF with 1.5 mill Kr, 01-Aug-1997 to 01-Aug-2000. PI: M. Givskov.
• Involvement of cell-cell communication in the pathogenesis of chronic Pseudomonas aeruginosa lung infection in cystic fibrosis. PI: M. Givskov. A DTU PhD grant 1.2 mill Kr.
• Involvement of cell-cell communication systems in coordinated behavior of bacteria. PI: M. Givskov. Supported by SSVF with 360.000 Kr, 01-Jan-1997 31-Dec-1999.
• Role of bacterial cell-to-cell communication in food quality deterioration and food quality preservation. Financed by STVF with 2 mill Kr, 01-Jul-1997 to 01-Jul-2001.
• Impact of small molecule mediated cell-cell communication on the efficacy of inoculant bacteria in the rhizosphere. Financed by EU with 1.4 mill Kr, 01-Sep-1996 to 31-Aug-1999.
• Effect of manure spreading on horizontal transmission of bacterial resistance genes. 1.2 mill Kr financed by the Ministry for Food and Agriculture for a PhD grant.
• Molecular analysis and characterization of pH and stationary phase inducible promoters from Lactococcus lactis. PhD grant, 1.2 mill Kr financed by ATV. 
• Cell communication and food deterioration, financed by STVF 2 mill Kr. Jan-2000 to 31-Dec-2002. PI's Lone gram and M.Givskov
• A new approach to the control of microbial activity.  PI: M. Givskov. Financed by STVF with 13.5 mill Kr (five-year frame program, prolongation for three additional years optional) from 01-Jan-2001 to 31-Dec-2005.
• A new approach to the control of microbial activity. PI: M. Givskov. Financed by The Villum-Kann Rasmussen Foundation 5.5 mill Kr., 01-May-2001 to 01-Oct-2004.
• Pseudomonas: pathogenicity and biotechnology. European elite PhD school denoted "Pseudomonas: pathogenicity and biotechnology" granted by Deutsche Forshungsgemeinshaft and the Danish Research Council to Givskov, Molin and Hoiby. 01-Jan-2001 to 31-Dec-2003. PhD grant to Givskov 1.2 mill Kr.
• Leo-incubator finances the establishment of QSI-Pharma for the design of novel, anti-microbial drugs: 14 mill Kr plus free administrative support. Jan-2002 to 01-Oct-2005.
• Center for elimination of biofilms on medical equipment. Jan-2004 to 31-Dec-2006. Innovation consortium in collaboration with The Technological Institute, The University of Aalborg, Coloplast Research A/S, Egalet A/S, Melitek A/S, PBN Medicals A/S and Radiometer Medical A/S. Givskov part 1.5 mill Kr.
• Drug hunting at the Great Barrier Reef, PI Givskov, fieldwork 0.15 mill Kr support from private foundations, August 2004.
• Microbial opportunistic Pathogens-a severe problem to human health. Danish Research Center. 25 mill Kr Jan-2004 to 31-Dec-2007. PI Søren Molin CBM, BioCentrum (DTU). Members: Michael Givskov, CBM, BioCentrum (DTU),Lone Gram Danish Institute for Fisheries Research (DFU), Niels Høiby, Rigshospitalet (RH), Hanne Ingmer, Dept of Veterinary Microbiology (KVL), Per Klemm, BioCentrum (DTU), Karen A. Krogfelt, Statens Serum Institut(SSI) & CBM BioCentrum (DTU), Niels B. Larsen, The Danish Polymer Centre (RISØ), Tim Tolker-Nielsen, CBM, BioCentrum (DTU),Bjarke B. Christensen, Danish Food Administration (IFSE). Givskov part 1.7 mill Kr.
• Garlic derived antimicrobials for treatment of CF patients. Marts-2006 to April-2008. PI Givskov. Supported by The German Mukoviszidose ev with 480.000 EUR (3.6 mill Kr).
• Confocal microscope 2006. PI Givskov. Danish Research Council FNU 1.2 mill Kr.
• October 15th  2006 to Marts 15th  2007. Grant from Mölnlycke Health Care R&D to PI Givskov 100.000 Kr.
• Bacterial infections on implants and in the lungs of experimental animals. October 16th  2006 to June 15th  2007. Grant fro UNSW Sydney to PI Givskov 344.400 Kr.
• Food constituents and impact on chronic infections. Jan-2007 to Jan-2011. PI Givskov. Supported by the Danish Strategic Research Council (Food and Health) with 14 mill Kr.
• Discovery of marine bioactive bacteria and natural products and their use to promote human health and safety.  Supported by the Danish Strategic Research Council (Food and Health) with 13.9 mill Kr and the Lundbeck foundation with 1.5 mill Kr. Jan-2008 to Jan-2012. PI Lone Gram. Givskov part 1.7 mill Kr.
• Center for Antimicrobial Research. Supported by the Danish Strategic Research Council PI Givskov. 27.5 mill Kr. Jan-2009 to Dec-2013
•  Total of 100 mill Kr over the past decade.

Kommentarer til publikationsliste

Publication list

• 1. Givskov, M., and Molin, S. (1984) Copy mutants of plasmid R1: Effects of base pair substitutions in the copA gene on the replica­tion control system. Mol Gen Genet. 194:286-292
• 2. Molin, S., Givskov, M., and Riise, E. (1985) Bac­terial enzymes. Patent DK 2100/85.
• 3. Givskov, M., Stougaard, P., Light, J., and Molin, S. (1987) Identi­fi­cation and characterization of muta­tions responsible for a runaway replication phenotype of plasmid R1. Gene 57:203-211.
• 4. Givskov, M., Olsen, L., and Molin, S. (1988) Cloning and ex­pres­sion in Escherichia coli of the gene for an extracellular phospholi­pase from Serratia liquefaci­ens. J Bacteriol 170: 5855-5862.
• 5. Molin, S., Givskov, M., Kristensen, C. S., Pej, A., and Eberl, L. (1992). A method of limiting the survival of genetically engine­ered microorga­nisms in their environment. USA Patent 07/863,2­61.
• 6. Givskov, M., and Molin, S. (1992) Expression of extracellular phospholi­pase from Serratia liquefa­ci­ens is growth phase-depen­dent, catabolite repressed and regulated by anaerobio­sis. Molec Microbiol 6:1363-1374.
• 7. Eberl. L., Givskov. M., and Schwab. H. (1992) The divergent pro­moters mediating transcription of the par locus of plasmid RP4 are subject to autoregula­tion. Molec Microbiol 6:1969-1979.
• 8. Givskov, M., and Molin, S. (1993) Secretion of Serratia liquefa­ciens phospholipase from Escherichia coli. Molec Microbiol 8:229-242.
• 9. Molin, S., Boe, L., Jensen, L. B., Kristensen, C. S., Givskov, M., Ramos, J.L., and Bej, A.K. (1993). Suicidal genetic elements and their use in biological containment of bacteria. Annu Rev Microbiol 47:139-166.
• 10. Givskov, M., Eberl, L., Møller, S., Poulsen, L. K., and Molin. S (1994) Responses to nutri­ent starvation in Pseudo­monas putida KT2442: Analysis of general cross-protection, cell shape, and macromole­cular content. J Bacteriol 176:7-14.
• 11. Givskov, M., Eberl, L., and Molin, S (1994) Responses to nutri­ent starvation in Pseudomonas putida KT2442: 2-Dimensio­nal electrofo­re­tic analysis of starvation and stress in­ducible proteins. J Bac­teriol 176:4816-4824.
• 12. Eberl. L., Kristensen. C., Givskov. M., Grohmann. E., Gerlitz. M., and Schwab. H. (1994) Analysis of the multimer resolution system encoded by the parCBA operon of broad-host-range plasmid RP4. Molec Micro­biol 12:131-141.
• 13. Ravn, P., Givskov, M., Eegholm, K. M., Madsen. S. M., and Boe. L. (1994). Observations on the formation of deletions on mono­meric and dimeric plasmids in Escherichia coli. Molec Microbiol 14:263-270.
• 14. Givskov, M., Eberl, L., Christiansen, G., Benedik, M.J., and Molin, S. (1995). Induction of phospholi­pase- and fla­gellar synthe­sis in Serratia liquefaci­ens is con­trolled by expres­sion of the flagellar ma­ster operon flhD. Molec Microbi­ol 15:445-454
• 15. Kristensen, C. S., Eberl, L., Sanchez-Romero, J. M., Givskov, M., Molin, S., and deLorenzo, V. (1995) Site-specific dele­tions of chromosomal DNA segments with the multimer resolu­tion system (mrs) of the broad-host-range plasmid RP4. J bacteri­ol 177:52­-58.
• 16. van Overbeek,­ L.S., Eberl, L., Givskov, M., Molin, S., and van Elsas, J.D. (1995) Survival of, and induced stress resistance in, carbon-starved Pseudomonas fluores­cens cells residing in soil. Appl Environ Microbiol 61:4202-4208
• 17. Kjelleberg, S., Steinberg, P., de Nys, R., Manefield, M., Givskov, M., and Gram, L. (1995) Microbiocide and microbial regulator. Australia patent application 94/450.
• 18. Eberl, L., Givskov, M., Møller, S., Christiansen, G., and Molin, S. (1996) Responses to phosphate starvation in Pseudomo­nas putida KT2442. Microbiol 142:155-163
• 19. Eberl, L., Christiansen, G., Molin, S., and Givskov, M.(1996) Differen­tiation of Serratia liquefaciens into swarm cells is controlled­ by the expression of the flhD master operon. J Bacteriol 178:554-559
• 20. Eberl, L., Winson, M.K., Sternberg, C., Stewart, G. S. A. B., Christi­ansen, G., Chhabra, S.R., Daykin, M., Williams, P., Moli­n, S., and Giv­sk­ov, M. (19­96) In­vol­ve­ment of N-acyl-L-homoserine lactone autoinducers in control of multicellular behavior of Serra­tia liquefaciens. Molec Micro­biol 20:127-136.
• 21. de Nys, R., M. Givskov, L. Gram, S. Kjelleberg, M. Manefield, R. Maximilien, and P. Steinberg 1996. Inhibiting microbial processes regulated by homoserine lactone - using furanone drivs., pref. from algae, e.g. to prevent motility, swarming and enzyme production in pathogenic bacteria. Patent WO9629392-A1.
• 22. Givskov, M., de Nys, R., Manefield, M., Gram, L., Maximilien, R., Eberl, L., Molin, S., Steinberg, P. D., and Kjelleberg, S. (1996) Eukaryotic interfer­ence with homoserine lactone mediated procary­otic signalling. J Bacteriol 178:6618-6622.
• 23. Gram, L., de Nys, R., Maximilien, R., Givskov, M., Steinberg, P. D., and Kjelleberg, S. (1996) Inhibitory effects of furanones from the red alga Delisea pulchra on swarming motility of Proteus mirabilis. Appl Environ Microbiol 62:4284-4287.
• 24. Eberl, L., Givskov, M., Poulsen, L. K., and Molin, S. (1997) Use of biolumines­cence for monitoring the viability of individual Pseudo­monas putida KT2442 cells. FEMS Microbiol Lett 149:129-132.
• 25. Givskov, M., Eberl, L., and Molin, S. (1997). Control of exoenzyme production, motility and cell differentiation in Serratia liquefaci­ens. FEMS Microbiol Lett 148:115-122 Review
• 26. Kjelleberg, S. Steinberg, P. D., Givskov, M., Manefield, M., and de Nys, R. (1997). Do marine products interfere with procaryotic AHL regulatory systems? Review Aquat Microbiol Ecol 13:85-93.
• 27. Givskov, M., Östling, J., Lindum, P. W., Eberl, L., Christiansen, G., Molin, S., and Kjelleberg, S. (1998). The participation of two seperate regulatory systems in controlling swarming motility of Serratia liquefaciens (J Bacteriol 180:742-745)
• 28. Møller, S., Sternberg, C., Andersen, J. B., Christensen, B. B., Ramos, J. L., Givskov, M., and Molin, S. (1998). In situ gene expression in mixed culture biofilms: evidence of metabolic interactions between community members (Appl Environ Microbiol 64: 721-732)
• 29. Andersen, J. B., Sternberg, C., Poulsen, L. K., Bjørn, S. P., Givskov, M., and Molin, S. (1998) New unstable variants of green fluorescent protein for studies of transient gene expression in Bacteria (Appl Environ Microbiol 64:2240-2246).
• 30. Christensen, B. B., Sternberg, C., Andersen, J. B., Eberl, L., Møller, S., Givskov, M., and Molin, S. (1998) Establishment of new genetic traits in a model community for degradation of benzyl alchohol. Appl Environ Microbiol 64:2247-2255.
• 31. Eberl, L., Ammendola, A., Geisenberger, O., Schulze, R., Givskov, M., Sternberg, C., Molin, S., and Schleifer, K. H. (1998) Use of green flourescent protein for online, single cell detection of bacteria introduced into activated sludge microcosms. Biofilm 3, 1
• 32. Ammendola, A., Geisenberger, O., Andersen, J. B., Givskov, M., Schleifer, K. H., and Eberl, L. (1998) Serratia liquefaciens swarm cells exhibit enhanced resistance to predation by Tetrahymena sp. FEMS Microbiol Lett 164:69-75
• 33. Maximilien, R., de Nys, R., Holmström, C., Gram, L., Givskov, M., Crass, K., Kjelleberg, S., and Steinberg, P. D. (1998) Chemical mediation of bacterial surface colonisation by secondary metabolites from the red alga Delisea pulchra. Aquat Microbiol Ecol 15:233-246.
• 34. Hansen, M. C., Tolker-Nielsen, T., Givskov, M., and Molin, S (1998) Biased 16S rDNA PCR amplification caused by interference from DNA flanking the template region. FEMS Microbiol Lett 26:141-149
• 35. Givskov, M., and Søgaard-Andersen, L. (1998) Kommunikation hos bakterier. Naturens verden 5:207-216. Review
• 36. Lindum, P. W, U. Anthoni, C. Christoffersen, L. Eberl, S. Molin, and M. Givskov. (1998). N-acyl-_L-homoserine lactone autoinducers control production of an extracellular surface active lipopeptide required for swarming motility of Serratia liquefaciens MG1. J Bacteriol 180: 6384-6388.
• 37. Molin, S., Nielsen, A.T. Christensen, B.B., Andersen, J.B., Licht, T.R., Tolker-Nielsen,T., Sternberg, C., Hansen, M.C., Ramos, C., and Givskov, M. (1999). Molecular ecology of biofilms. In: Biofilms, 2^nd edition (ed. James Bryers), J Wiley & Sons, Inc. BooK chapter.
• 38. Manefield, M., DeNys, R., Kumar, N., Read, R., Givskov, M., Steinberg, P., and Kjellebjerg, S (1999) Evidence that halogenated furanones from Delisea pulchra inhibit acylated homoserine lactone (AHL)-mediated gene expression by displacing the AHL signal from its receptor protein Microbiology 145: 283-291
• 39. Madsen, S., Arnau, J., Vrang, A., Givskov, M., and Israelsen, H. (1999) Molecular analysis and characterization of a pH and stationary phase inducible promoter, P170, from Lactococcus lactis Molec Microbiol 32:75-87.
• 40. Christensen, BB., Sternberg, C., Andersen, JB., Palmer, RJ., Nielsen, AT., Givskov, M., and Molin, S (1999) Molecular tools in physiological studies of microbial biofilms. Meth Enzymol 310:20-42
• 41. Eberl, L., Molin, S., and Givskov, M (1999). Surface motility in Serratia liquefaci­ens. J Bacteriol 181:1703-1712. Review
• 42. Mathee, K., Ohman, D., E, Ciofu, O., Sternberg, C., Lindum, P., Campbell, J., Jensen, P., Givskov, M., Molin, S., Høiby, N., Kharazmi, A. (1999) Mucoid Conversion of Pseudomonas aeruginosa by Hydrogen Peroxide: A Potential Mechanism for Virulence Activation in the Cystic Fibrosis Lung Microbiology 145: 1349-1357.
• 43. Gram, L., Christensen, A. B., Ravn, L., Molin, S., and Givskov, M. (1999) Production of acylated homoserine lactones by psychrotrophic Enterobacteriaceae isolated from foods. Appl. Envir. Microbiol. 65: 3458-3463
• 44. Rice, S.A., Givskov, M, Steinberg, and Kjelleberg, S (1999) Bacterial signals and antagonists: The interaction between bacteria and higher organisms. J Mol Microbiol Biotechnol 1: 23-31.
• 45. Molin, S., and Givskov, M (1999) Application of molecular tools for in situ monitoring of bacterial growth activity. Environ Microbiol 1:383-391.
• 46. Sternberg, C., Christensen, BB., Johansen, T., Andersen, JB., Givskov, M., and Molin, S (1999) Distribution of bacterial growth activity in flow-chamber biofilms Appl Eviron Microbiol 65:4108-4117.
• 47. Holden MT, Ram Chhabra S, De Nys R, Stead P, Bainton NJ, Hill PJ, Manefield M, Kumar N, Labatte M, England D, Rice S, Givskov M, Salmond GP, Stewart GS, Bycroft BW, Kjelleberg S, Williams P (1999) Quorum-sensing cross talk: isolation and chemical characterization of cyclic dipeptides from Pseudomonas aeruginosa and other Gram-negative bacteria. Molec Microbiol 33:1254-1266
• 48. Givskov, M., Andersen, J. B., Henzer, M., Heidorn, A., Molin, S., Eberl, L., deNys, R., Manefield, M., Steinberg, P. D., Kjelleberg, S., Wu, H., Song, Z., and Høiby, N. (1999). Quorum sensing and eukaryote-prokaryote interactions. Clin Microbiol Infect 5:6-7 . Review
• 49. Bees, M. A., Andresèn, P., Mosekilde, E., and Givskov, M. (2000) The interaction of thin-film flow, bacterial swarming and cell differentiation in colonies of Serratia liquefaciens. J Math Biology 40:27-63.
• 50. Krogfelt, K. A., Hjulgaard, M., Sørensen, K., Cohen, S., and Givskov, M. (2000) Escherichia coli BJ4 colonization of the streptomycin-treated mouse large intestine is independent of rpoS-gene function. Infect and Immun 68: 2518-2524.
• 51. Geisenberger, O., M. Givskov, K. Riedel, N. Høiby, B. Tümmler, and L. Eberl. (2000). Production of N-acyl-L-homoserine lactones by P. aeruginosa isolates from chronic lung infections associated with cystic fibrosis. FEMS Microbiol. Lett. 184:273-277.
• 52. Tolker-Nielsen, T., Christensen, A. B., Eberl, L., Rasmussen, T. B., Sternberg, C., Molin, S., and Givskov, M. (2000) Assessment of flhDC mRNA levels in individual Serratia liquefaciens swarm cells. J Bacteriol 182:2680-2686.
• 53. Kjelleberg S, and Givskov M (2000) Communication systems as targets for biological control. Environ microbiol 2: 5-5
• 54. Eberl, L., Ammendola, A., Rothballer, M. H., Givskov, M., Sternberg, C., Kilstrup, M., Schleifer, K-H., and Molin, S. (2000) Inactivation of gltB Abolishes Expression of the Assimilatory Nitrate Reductase Gene (nasB) in Pseudomonas putida KT2442J. Bacteriol. 182: 3368-3376
• 55. Charlton, T. S., de Nys, R., Netting, A., Kumar, N., Hentzer, M., Givskov, M., Kjelleberg, S (2000) A novel and sensitive method for the quantification of N-3-oxoacyl homoserine lactones using gas chromatography-mass spectrometry: Application to a model bacterial biofilm. Environ Microbiol, 2: 530-541 .
• 56. Charlton, T., Givskov, M., deNys, R., Andersen, J. B., Hentzer, M., Rice, S., and Kjelleberg, S. (2000) Genetic and Chemical Tools for Investigating Signaling Processes in Biofilms (Methods in Enzymology 336:108-128).
• 57. Heydorn, A., Nielsen, A. T., Hentzer, M., Sternberg, C., Givskov, M., Ersbøll, B. K., Molin, S. (2000). Quantification of biofilm structures by the novel computer program comstat Microbiology 146: 2395-2407.
• 58. Heydorn, A., B. K. Ersboll, M. Hentzer, M. R. Parsek, M. Givskov & S. Molin. (2000). Experimental reproducibility in flow-chamber biofilms Microbiology; 146: 2409-2415.
• 59. Wu, H., Song, Z., Henzer, M., Andersen, J. B, Heidorn, A., Mathee, K., Moser, C., Molin, S., Høiby, N., and Givskov, M. (2000). Detection of N-acyl-homoserine lactones in lung tissues of mice infected with Pseudomonas aeruginosa. Microbiol 146: 2481-2493
• 60. Rasmussen, T. B., Manefield, M., Andersen,J.B., Eberl, L., Anthoni, U., Christophersen, C., Steinberg, P., Kjelleberg, S., and Givskov, M. (2000). How Delisea pulchra furanones affect quorum-sensing and swarming motility in Serratia liquefaciens MG1. Microbiology 146: 3237-3244.
• 61. DeNys, R., Rice, S., Manefield, M., Srinivasan, S., McDougald, D., Loh, A., Lindum, P., Östling, J., Givskov, M., Steinberg, P. D., and Kjelleberg, S (2000) Cross-talk in bacterial extracellular systems. In: Microbial ecosystem: New Frontiers. Bell, C. R., Brylinsky, P., and Johnson, P (eds.). Atlantic Canada Society for Microbiology, Halifax. pp. 279-285.
• 62. Andersen, J. B., Heydorn, A., Hentzer, M., Eberl, L., Geisenberger, O., Molin, S., and Givskov, M (2001) gfp based N-acyl-homoserine-lactone monitors for detection of bacterial communication. App Environ Microbiol, 67: 575-585.
• 63. Riedel, K., Ohnesorg, T., Krogfelt, K. A., Hansen, T. S., Omori, K., Givskov, M., and Eberl, L. (2001). N-Acyl-L-homoserine lactone-mediated regulation of the Lip secretion system in Serratia liquefaciens MG1. J. Bacteriol 183: 1805-1809.
• 64. Wu, H., Song, Z., Givskov, M., Doring, G., Mathee, K., Rygaard, J., and Høiby, N. (2001) Pseudomonas aeruginosa mutations in lasI and rhlI quorum sensing systems result in milder chronic lung infection. Microbiology.147:1105-13.
• 65. Gram, L., and Givskov, M (2001) Kommunikation hos bakterier - i mad og andre steder. Naturens Verden 84:18-25. Review.
• 66. Ravn, L., A.B. Christensen, S. Molin, M. Givskov and L. Gram. (2001). Methods for identifying and quantifying acylated homoserine lactones produced by Gram-negative bacteria and their application in studies of AHL-production kinetics. J Microbiol Methods 44: 239-251.
• 67. Huber, B., Riedel, K., Hentzer, M., Heydorn, A., Gotschlich, A., Givskov, M., Molin, S., and Eberl, L. (2001) The cep quorum-sensing system of Burkholderia cepacia H111 controls biofilm formation and swarming motility. Microbiol 147:2517-28.
• 68. Hentzer, M., Teitzel, G., Balzer, G., Heydorn, A., Molin S., Givskov, M., and Parsek, M. R. (2001) Alginate overproduction affects Pseudomonas aeruginosa biofilm structure and function. J. Bacteriol 183:5395-401.
• 69. Riedel, K., Hentzer, M., Geisenberger, O., Huber, B., Steidle, A., Wu, H., Høiby, N., Givskov, M., Molin, S., and Eberl, L. (2001). N-Acyl homoserinelactone-mediated communication between Pseudomonas aeruginosa and Burkholderia cepacia in mixed biofilms. Microbiol 147:3249-62.
• 70. Steidle, A., Sigl, K., Schuhegger, R., Ihring, A., Schmid, M., Stoffels, M., Riedel, K., Givskov, M., Hartmann, A., Langebartels, C., Eberl, L. (2001) Visualization of N-Acylhomoserine Lactone (AHL)-mediated cell-cell communication between bacteria colonizing the tomato rhizosphere Appl. Environ. Microbiol. 67: 5761-5770
• 71. Manefield, M., Welch, M., Givskov, M., Salmond, G. P. C., and Kjelleberg, S. (2001). Halogenated furanones from the red alga, Delisea pulchra, inhibit carbapenem antibiotic synthesis and exoenzyme virulence factor production in the phytopathogen Erwinia carotovora. FEMS Microbiol Lett. 27 205:131-8.
• 72. Olsen, J. A., R. Severinsen, T. B. Rasmussen, M. Hentzer, M. Givskov and J. Nielsen (2002) Synthesis of New 3- and 4-Substituted Analogs of Acyl Homoserine Lactone Quorum Sensing Autoinducers. Bioorg Med Chem Lett.12:325-8.
• 73. Hentzer, M., K. Riedel, T. B. Rasmussen, A. Heydorn, J. B. Andersen, M. R. Parsek, S. Rice, L. Eberl, S. Molin, S., Høiby, N., Kjelleberg, and M. Givskov (2002). Inhibition of quorum sensing in Pseudomonas aeruginosa biofilm bacteria by a halogenated furanone compound. Microbiol 148:87-102.
• 74. Manefield, M., Rasmussen, T. B., Kumar, N., Hentzer, M., Andersen, J. B., Steinberg, P., Kjelleberg, S., and Givskov M (2002). Halogenated furanones inhibit quorum sensing through accelerated LuxR turnover. Microbiol 148, 1119-1127.
• 75. Bees, M. A., Andrèsen, P., Mosekilde, E., and Givskov, M. (2002) Quantitative effects of medium hardness and nutrient availability on the swarming of Serratia liquefaciens. Bull Math Biol.64:565-87.
• 76. Hentzer, M., Givskov, M., and Parsek, M. R. (2002) Targeting Quorum Sensing for Treatment of Chronic Bacterial Biofilm Infections. Lab Medicine 33:295-306.
• 77. Gram, L., Ravn, L, Rasch, M., Bruhn, J.B., Christensen, A. B., and Givskov, M (2002) Food spoilage - interactions between food spoilage bacteria. International Journal of Food Microbiology 78: 79-97.
• 78. Heydorn, A., Ersbøll, B., Kato, J., Hentzer, M., Parsek, M. R., Tolker-Nielsen, T., Givskov, M., and Molin, S. (2002) A Statistical Analysis of Pseudomonas aeruginosa Biofilm Development: Impact of Mutations in Genes Involved in Twitching Motility, Cell-to-cell Signaling and Stationary Phase Gene Expression. Appl Environ Microbiol.68:2008-17.
• 79. Laux, D. C., Corson, J. M., Givskov, M., Hentzer, M., Møller, N., Olson, J. C., Krogfelt, K. A., Goldberg, J. B., and Cohen, P. S. (2002) Lysophosphatidic Acid Regulation of Pseudomonas aeruginosa Elastase and LasA. Microbiol 148: 1709-1723
• 80. Schembri, M. A., Givskov, M., and Klemm, P (2002). An Attractive Surface: Gram-negative Bacterial Biofilms. Sci STKE. 14 (132):RE6. Review
• 81. Koch, B., Nielsen, T. H., Sørensen, D., Andersen, J. B., Christophersen, C., Molin, S., Givskov, M., Sørensen, J., Nybroe, O. (2002) Lipopeptide production in Pseudomonas sp. strain DSS73 is regulated by components of sugarbeet seed exudate via the Gac two-component regulatory system. Appl Environ Microbiol 68:4509-16.
• 82. Nielsen J and Givskov M (2002) Compounds and methods to control bacterial virulence. (PCT patent application).
• 83. Givskov, M., Hentzer, M., Kjelleberg, S (2002) A method of causing sloughing (Australian patent application).
• 84. Nielsen, T. H., D. Sørensen, C. Tobiasen, J. B. Andersen, P. S. Lübeck, B., C. Christophersen, S. Molin, M. Givskov, and J. Sørensen (2002). Antibiotic and biosurfactant properties of cyclic lipopeptides produced by soil fluorescent Pseudomonas spp. from two Danish agricultural soils. Appl Environ Microbiol.68:3416-23.
• 85. Bagge N, Ciofu O, Hentzer M, Campbell JI, Givskov M, Hoiby N. (2002). Constitutive high expression of chromosomal beta-lactamase in Pseudomonas aeruginosa caused by a new insertion sequence (IS1669) located in ampD. Antimicrob Agents Chemother. 46(11):3406-11.
• 86. Agersø, Y., Jensen, L. B., Givskov, M., and Roberts, M. C. (2002) The identification of the tetracycline resistance gene tet(M), on a Tn916-like transposon, in the Bacillus cereus group. FEMS Microbiol Lett.214:251-6.
• 87. Huber B, Riedel K, Köthe1 M, Givskov M, Molin S and Eberl L (2002) Genetic Analysis of functions involved in the late stages of biofilm development in Burkholderia cepacia H111. Mol Microbiol. 46:411-26.
• 88. Givskov, M., and Rasmussen, T. B. (2002) Quorum sensing hæmmere: en ny måde at bekæmpe bakterielle infektioner på. Dansk Kemi 83(11):32-36. Review
• 89. Steidle A, Allesen-Holm M, Riedel K, Berg G, Givskov M, Molin S, Eberl L. (2002) Identification and Characterization of an N-Acylhomoserine Lactone-Dependent Quorum-Sensing System in Pseudomonas putida Strain IsoF. Appl Environ Microbiol. 68:6371-82.
• 90. Christensen, A. B., Riedel, K., Eberl, L., Flodgaard, L, R., Molin, S., Gram, L., and Givskov, M. (2003) Quorum sensing directed protein expression in Serratia proteamaculans B5a. Microbiol 149:471-483.
• 91. Andersen JB, Koch B, Nielsen TH, Sørensen D, Hansen M, Nybroe O, Christophersen C, Sørensen J, Molin S and Givskov, M (2003) Surface motility in Pseudomonas sp. DSS73 is required for efficient biological containment of the root pathogenic microfungi Rhizoctonia solani and Pythium ultimum. Microbiol 149(pt1):37-46.
• 92. Hentzer, M., Eberl, L., Nielsen J., and Givskov, M (2003) Quorum sensing: a novel target for treatment of biofilm infections. Biodrugs 17(4):241-250. Review
• 93. Hjemlmgaard, T., Persson, T., Rasmussen, T. B., Givskov, M., and J. Nielsen (2003) Synthesis of furanone-based natural product analogues with quorum sensing antagonist activity. Bioorg Med Chem 69(7):3261-3271
• 94. M. Manefield, S. Kjelleberg, and M. Givskov. (2003) Controlling bacterial infection through AHL mediated gene expression. Curr Med Chemistry-Anti-Infect Agents. 2:213-218
• 95. Hentzer, M., Wu, H., Andersen, J.B., Riedel, K., Rasmussen, T.B., Bagge, N., Kumar, N., Schembri, M., Song, Z., Kristoffersen, P., Manefield, M., Eberl, L., Costerton, J.W., Molin, S., Steinberg, P., Kjelleberg, S., Høiby, N., and Givskov M. (2003) Attenuation of Pseudomonas aeruginosa virulence by quorum sensing inhibitors. EMBO J 22(15):3803-3815
• 96. Riedel, K., Talker-Huiber, D., Givskov, M., Schwab, H., Eberl, L. (2003) Identification and characterization of a GDSL esterase located proximal to the swr quorum-sensing system of Serratia liquefaciens MG1. Appl Environ Microbiol.69(7):3901-10.
• 97. Wu, H., Song, Z., Hoiby, N., and Givskov, M (2003) Bacterial cell-cell communication - Gram negative bacterial quorum sensing systems. Prog Nat Sci (China) 13(7): 679-687. Review
• 98. Webb, J.S., Thompson, L., James, S., Charlton, T., Tolker-Nielsen, T., Koch, B., Givskov, M., Kjelleberg, S. (2003). Cell death in Pseudomonas aeruginosa biofilm development. J Bacteriol 185(15):4585-92.
• 99. Song, Z., Wu, H., Givskov, M., and Hoiby, N. (2003) Bacterial biofilms and antibiotic resistance. Prog in Nat Sci, China 13(10):1015-1021. Review
• 100. Flodgaard RL, Christensen AB, Molin S, Givskov M, Gram L. 2003 Influence of food preservation parameters and associated microbiota on production rate, profile and stability of acylated homoserine lactones from food-derived Enterobacteriaceae. Int J Food Microbiol. 84(2):145-156
• 101. Hentzer, M., and Givskov, M (2003) Pharmacological Inhibition of Quorum Sensing for Treatment of Chronic Bacterial Infections. J Clin Invest 112(9):1300-7. Review
• 102. Labbate, M., Queck, S.Y., Rice, S. A., Givskov, M., and Kjelleberg, S. (2004) Quorum sensing controlled biofilm development in Serratia liquefaciens MG1. J Bacteriol 186(3): 692-698.
• 103. Webb, J.S, Givskov M., Kjelleberg S (2003) Bacterial biofilms: prokaryotic adventures in multicellularity. Curr Opin Microbiol. 2003 Dec; 6(6):578-85. Review.
• 104. Arevalo-Ferro C, Hentzer M, Reil G, Görg A, Kjelleberg S, Givskov M, Riedel K, Eberl L (2003) Identification of quorum sensing regulated proteins in the opportunistic pathogen Pseudomonas aeruginosa by proteomics. Environ Microbiol.5(12):1350-1369.
• 105. Rasch M, Buch C, Austin B, Slierendrecht W.J, Ekmann K.S, Larsen J.L, Johansen C, Riedel K, Eberl L, Givskov M and Gram L. (2004). An inhibitor of bacterial quorum sensing reduced mortalities caused by vibriosis in rainbow trout (Oncorhynchus mykiss, Walbaum) Syst. Appl. Microbiology 27: 350-359.
• 106. Wu, H., Song, Z., Givskov, M and Hoiby, N. (2004). Effects of quorum-sensing on immunoglobulin G responses in a rat model of chronic lung infection with Pseudomonas aeruginosa. Microbes Infect. 6(1): 34-7.
• 107. Bagge N, Hentzer M, Andersen, J.B, Ciofu O, Givskov M, and Hoiby N. (2004) Dynamics and spatial distribution of beta-lactamase expression in Pseudomonas aeruginosa biofilms.Antimicrob Agents Chemother. 48(4):1168-74.
• 108. Bagge N, Schuster M, Hentzer M, Ciofu O, Petersen B. P., Duus J.Ø., Givskov M, Greenberg E.P., and Hoiby N. (2004). Pseudomonas aeruginosa biofilms exposed to imipenem exhibit changes in global gene expression and beta-lactamase and alginate production. Antimicrob Agents Chemother. 48(4):1175-87.
• 109. Wu H, Song Z, Hentzer M, Andersen J.B, Molin S, Givskov M, and Høiby N. 2004 Synthetic furanones inhibit quorum-sensing and enhance bacterial clearance in Pseudomonas aeruginosa lung infection in mice. J Antimicrob Chemother. 53(6):1054-61
• 110. Zhu, H., Bandara, R., Conibear, T. C., Thuruthyil, S.J., Rice, S.A., Kjelleberg, S., Givskov, S., and Willcox, M. D. (2004). Pseudomonas aeruginosa with LasI quorum-sensing deficiency during corneal infection. Invest Ophthalmol Vis Sci. 45(6):1897-903
• 111. Hentzer, M., Eberl, L., and Givskov, M. (2004) Quorum sensing in Biofilms: Gossip in the slime world? pp 118-140. In Microbial biofilms, Eds M. Ghannoum & G.O'Toole, ASM Press, Washington, D.C.Book chapter.
• 112. Givskov, M (2004) Intelligent bakteriebekæmpelse. Aktuel Naturvidenskab 2:25-27. Review
• 113. Danhorn, T., Hentzer,M., Givskov,M., Parsek,M. R., Fuqua, C. (2004) Phosphorus Limitation Enhances Biofilm Formation of the Plant Pathogen Agrobacterium tumefaciens through the PhoR-PhoB Regulatory System J. Bacteriol. 186:1448-03
• 114. Bruhn, J.B., Christensen, A.B., Flodgaard, L.R., Nielsen, K.F., Larsen, T.O., M. Givskov and Gram L. (2004). Presence of acylated homoserine lactones (AHLs) and AHL producing bacteria in meat and the potential role of AHL in spoilage of meat. Appl. Environ. Microbiol. 70:4293-4302
• 115. Persson, T., Johansen, S.K., Martiny, L., Givskov, M., and Nielsen, J. (2004) Synthesis of carbon-14 labelled (5Z)-4-bromo-5-(bromomethylene)-2(5H)-furanone: a potent quorum sensing inhibitor. J Label Compd Radiopharm. 47:627-634.
• 116. Chhabra, S.R., Eberl, L., Givskov, M., Philip, B., Williams, P and Cámara, M. (2005) Extracellular communication in bacteria. Pheromones and other Semiochemicals Vol 2. (Ed. S.. Schulz) Springer-Verlag. Topics in Current Chemistry 240: 279-315. Book chapter.
• 117. Rasmussen TB, Bjarnsholt T, Skindersoe ME, Hentzer M, Kristoffersen P, Köte M, Nielsen J, Eberl L, Givskov M. 2005. Screening for quorum-sensing inhibitors (QSI) by use of a novel genetic system, the QSI selector. J Bacteriol. 187(5):1799-814.
• 118. Bjarnsholt T., Jensen P.Ø., Burmølle M., Hentzer M., Haagensen J.A., Hougen H.P., Calum H., Madsen K.G., Moser C., Molin S., Hoiby N., Givskov M. 2005. Pseudomonas aeruginosa tolerance to tobramycin, hydrogen peroxide and polymorphonuclear leukocytes is quorum-sensing dependent. Microbiology.151:373-83.
• 119. Persson T, Hansen TH, Rasmussen TB, Skinderso ME, Givskov M, Nielsen J. 2005 Rational design and synthesis of new quorum-sensing inhibitors derived from acylated homoserine lactones and natural products from garlic. Org Biomol Chem. 21;3(2):253-62.
• 120. Jelsbak L, Givskov M, Kaiser D. 2005 Enhancer-binding proteins with a forkhead-associated domain and the {sigma}54 regulon in Myxococcus xanthus fruiting body development. Proc Natl Acad Sci U S A. 22;102(8):3010-5.
• 121. Hoffmann, N., Rasmussen, T.B., Jensen, P.Ø., Stub, C., Hentzer, M., Molin, S., Ciofu, O., Givskov, M., Johansen, H.K., Høiby, N. (2004). A Novel Mouse Model of Chronic Pseudomonas aeruginosa Lung Infection Mimicking Cystic Fibrosis. Infection and Immunity 73(4):2504-14..
• 122. Rasch, M., J.B. Andersen, K.F. Nielsen, L. R. Flodgaard, H. Christensen, M. Givskov and L. Gram 2005. Involvement of bacterial quorum sensing signals in spoilage of bean sprouts. Appl. Environ. Microbiol. 71(6):3321-30.
• 123. Flodgaard, L.R., P. Dalgaard, J.B. Andersen, K.F. Nielsen, M. Givskov and L. Gram 2005. Non-bioluminescent strains of Photobacterium phosphoreum produce the cell-to-cell communication signal 3-hydroxyl-octanoyl homoserine lactone. Appl. Environ. Microbiol. 71(4):2113-20.
• 124. Hentzer,M., Eberl,L., Givskov,M. (2005) Transcriptome Analysis of Pseudomonas aeruginosa. Biofilms. 2(1): 37-61.
• 125. Hentzer, M., and Givskov, M. (2005) Jamming bacterial communication: new strategies to combat bacterial infections and the development of biofilms. In Bacterial Cell-to-Cell Communication:Role in Virulence and Pathogenesis.Demuth DR, Lamont R(eds.), Cambridge UniversityPress, Cambridge, UK. Book chapter.
• 126. Rasmussen, T.B., Skindersoe, M.E., Bjarnsholt, T., Phipps, R.K., Christensen, K.B., Andersen, J.B., Larsen, T.O., Hentzer, M., Eberl, L., and Givskov, M. (2005) Identity and Effects of Quorum Sensing Inhibitors Produced by Penicillium Species. Microbiol. 151 (5):1325-40.
• 127. Bragonzi, A., Worlitzsch, D., Pier, G. B., Hentzer, M., Givskov, M., Conese, M., and Döhring, G (2005). Non-mucoid Pseudomonas aeruginosa expresses alginate in the lungs of patients with cystic fibrosis and in a murine model. Journal Infectious Diseases 192(3):410-9.
• 128. Koch,B., Liljefors, T., Persson, T., Nielsen,J., Kjelleberg, S., and Givskov, M. (2005) The LuxR receptor: the sites of interaction with quorum sensing signals and inhibitors. Microbiol. 151(Pt 11):3589-602.
• 129. Bjarnsholt, T., Jensen, P. Ø., Rasmussen, T.B., Christophersen, L., Calum, H., Hentzer, M., Hougen, H-P., Rygaard, J., Moser, C., Eberl, L., Høiby, N., and Givskov, M. (2005). Garlic which blocks the Pseudomonas aeruginosa communication systems, promotes rapid clearing of pulmonary Pseudomonas aeruginosa infections. Microbiol. 151(Pt 12):3873-80.
• 130. Persson T, Givskov M, Nielsen J. (2005) Quorum sensing inhibition: Targeting chemical communication in Gram-negative bacteria. Curr Med Chem. 12(26):3103-15.
• 131. Rasmussen, T.B., Givskov, M. (2006) Quorum sensing Inhibitors as anti-pathogenic drugs. Int Journal Medical Microbiol. 296(2-3):149-61.
• 132. Schreiber K, Boes N, Eschbach M, Jaensch L, Wehland J, Bjarnsholt T, Givskov M, Hentzer M, Schobert M. (2006). Anaerobic survival of Pseudomonas aeruginosa by pyruvate fermentation requires an Usp-type stress protein. J Bacteriol. 188(2):659-68.
• 133. Allesen-Holm M, Barken KB, Yang L, Klausen M, Webb JS, Kjelleberg S, Molin S, Givskov M, Tolker-Nielsen T. (2006) A characterization of DNA release in Pseudomonas aeruginosa cultures and biofilms. Mol Microbiol. 59(4):1114-28.
• 134. de Nys, R., M. Givskov, N. Kumar, S. Kjelleberg, P.D. Steinberg (2006). Furanones. Progress in Molecular and Subcellular Biology. 42:55-86. Subseries Marine Molecular Biotechnology. N. Fusetani, A.S. Clare (Eds.): Antifouling Compounds. Springer-Verlag Berlin Heidelberg 2006 ISBN 3-540-30014-7. Review.
• 135. Rasmussen, T.B., and Givskov, M (2006) Quorum sensing inhibitors: a bargain of effects. Microbiol 152. 895-904. Review.
• 136. Shrout, J. D., Chopp, D.L., Just, C.L., Hentzer, M., Givskov, M., and Parsek, M.R (2006) The impact of quorum sensing and swarming motility on Pseudomonas aeruginosa biofilm formation is nutritionally conditional. Mol Microbiol. 2006 62(5):1264-77.
• 137. Bjarnsholt, T., and Givskov, M (2007). The role of quorum sensing in the pathogenicity of the cunning aggressor Pseudomonas aeruginosa. Anal Bioanal Chem., 387, 2: 409-14.
• 138. Kastbjerg VG, Nielsen KF, Dalsgaard I, Rasch M, Bruhn JB, Givskov M, Gram L.(2007) Profiling acylated homoserine lactones in Yersinia ruckeri and influence of exogenous acyl homoserine lactones and known quorum-sensing inhibitors on protease production. J Appl Microbiol. 102(2):363-74.
• 139. Rasch, M., T.B. Rasmussen, J.B. Andersen, T. Persson, J. Nielsen, M. Givskov and L. Gram (2007). Well-known quorum sensing inhibitors do not affect bacterial quorum regulated bean sprout spoilage. J Appl Microbiol. 102(3):826-37
• 140. Rasch, M., V.G. Kastbjerg, I. Dalsgaard, J.B. Bruhn, M. Givskov and L. Gram (2007). Quorum sensing signals are produced by Aeromonas salmonicida and quorum sensing inhibitors can reduce production of a potential virulence factor. Dis Aquat Organ. 13;78(2):105-13.
• 141. Hjelmgaard, T, Givskov, M and Nielsen, J (2007). Expedient synthesis of Pyrrothine natural products and analogs. Bioorg. Med. Chem. Jan 21;5(2):344-8.
• 142. Fexby, F., Bjarnsholt, T., Jensen, P.Ø., Roos,V., Høiby,N., Givskov,M and Klemm, P. A (2007). Biological Trojan Horse: Antigen 43 Provides Specific Bacterial Uptake and Survival in Human Neutrophils. Infect Immun. 75(1):30-4.
• 143. Labbate, M., Zhu, H., Thung, L., Bandara, R., Larsen, M.R., Willcox, M.D.P., Givskov, M., Rice, S.A., Kjelleberg, S. (2007) Quorum sensing regulation of adhesion in Serratia marcescens MG1 is surface dependent. J. Bacteriol 189(7):2702-11
• 144. Van Houdt R, Givskov M, Michiels CW. (2007) Quorum sensing in Serratia. FEMS Microbiol Rev. FEMS Microbiol Rev. 31(4):407-24. Review.
• 145. Bjarnsholt, T., and Givskov, M (2007). Quorum-sensing blockade as a strategy for enhancing host defences against bacterial pathogens. Philos Trans R Soc Lond B Biol Sci. Jul 29;362(1483):1213-22. Review
• 146. Yang L, Barken KB, Skindersoe ME, Christensen AB, Givskov M, Tolker-Nielsen T. (2007) Effects of iron on DNA release and biofilm development by Pseudomonas aeruginosa. Microbiology. 153(Pt 5):1318-28.
• 147. Jensen PØ, Bjarnsholt T, Phipps R, Rasmussen TB, Calum H, Christoffersen L, Moser C, Williams P, Pressler T, Givskov M, Høiby N. 2007 Rapid necrotic killing of polymorphonuclear leukocytes is caused by quorum-sensing-controlled production of rhamnolipid by Pseudomonas aeruginosa. Microbiology. 153(Pt 5):1329-38.
• 148. Christensen, L. D., Moser, C., Jensen P.Ø., Rasmussen, T.B., Christophersen, L., Kjelleberg, S., Kumar, N., Høiby, N., Givskov, M and Bjarnsholt, T. (2007).The impact of Pseudomonas aeruginosa Quorum Sensing on biofilm persistence in an in vivo intraperitoneal foreign-body infection model. Microbiol. 153(Pt 7):2312-20.
• 149. Bourne, D., Webster, N., Payne, M., Hoj, L., Skindersøe, M., Givskov, M. and Hall, M. (2007). Microbiological aspects of phyllosoma rearing of the ornate rock lobster Panulirus ornatus. Aquaculture. 268 (1-4): 274-287
• 150. Kjelleberg, S., and Givskov, M (Eds) (2007). The Biofilm Mode of Life: Mechanisms and Adaptations. Horizon Bioscience, Norfolk NR18 0JA U.K. Book chapter
• 151. Bjarnsholt, T., Kirketerp-Møller, K., Kristiansen, S., Phipps, R., Nielsen, A. K., Jensen, P.Ø., Høiby, N., and Givskov, M (2007) Silver against Pseudomonas aeruginosa biofilms. APMIS 115(8):921-8.
• 152. Hoffmann N, Lee B, Hentzer M, Rasmussen TB, Song Z, Johansen HK, Givskov M, Hoiby N. 2007 Azithromycin blocks quorum sensing and alginate polymer formation and increases the sensitivity to serum and stationary growth phase killing of P. aeruginosa and attenuates chronic P. aeruginosa lung infection in Cftr -/--mice. Antimicrob Agents Chemother. 51:3677-3687.
• 153. Rice SA, McDougald D, Givskov M, Kjelleberg S. (2007) Detection and inhibition of bacterial cell-cell communication. Methods Mol Biol.431:55-68.
• 154. Høiby N, Johansen HK, Ciofu O, Jensen PØ, Bjarnsholt T, Givskov M. 2007) Foreign body infections--biofilms and quorum sensing] Ugeskr Laeger. 26;169(48):4163-6. Review. Danish.
• 155. Bjarnsholt, T., Kirketerp-Møller, K., Jensen, P.Ø., Madsen, K.G., Phipps, R., Krogfelt, K., Høiby, N., and Givskov, M (2008) Why chronic wounds won't heal: a novel hypothesis. Wound Repair Regen.16(1):2-10.
• 156. Bjarnsholt, T and Givskov, M (2008) Quorum sensing inhibitory drugs as the next generation of anti-microbial compounds: Will it be worth the effort? Current Infectious Disease Reports. 10(1): 22-28. Review.
• 157. Kjelleberg, S., McDougald, D., Rasmussen, T. B., Givskov, M Quorum-sensing inhibition. In Chemical communication among bacteria, eds S.C.Winans and B.J.Bassler 2008 ASM Press, Washington DC. Book chapter.
• 158. Skindersoe, M. E., Epstein-Ettinger, P., Rasmussen, T.B., Bjarnsholt, T., de Nys, R., and Givskov, M. (2008) Quorum sensing antagonism from marine organisms. Mar Biotechnol (NY). 10(1):56-63.
• 159. Niels Høiby, Helle Krogh Johansen, Oana Ciofu, Claus Moser, Peter Ø. Jensen, Thomas Bjarnsholt, Søren Molin, Michael Givskov (2008) The clinical impact of bacterial biofilms. Accepted for publication in Annals of medicine. Review.
• 160. Balaban, N., Givskov, M Costerton, J.W, et al (2008). Control of Biofilm Infections by Signal Manipulation. Springer series on Biofilms ISSN 1863-9607. Springer-Verlag Berlin-Heidelberg. 4 Book chapters.
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• 164. Barken, K.B., Pamp, S.J., Yang, L., Gjermansen, M., Bertrand, J., Klausen, M., Givskov, M., Whitchurch, C., Engel, J., and Tolker-Nielsen, T. 2008 Roles of type IV pili, flagellum-mediated motility, and extracellular DNA in the formation of mature multicellular structures in Pseudomonas aeruginosa biofilms. ENVIRONMENTAL MICROBIOLOGY 10(9): 2331-2343.
• 165. Søren Kristiansen, Thomas Bjarnsholt, Dinah Adeltoft, Peter Ifversen and Michael Givskov. 2008. The Pseudomonas aeruginosa autoinducer dodecanoyl-homoserine lactone inhibits the polyamine synthesis in human cells. APMIS 116 (5): 361-371
• 166. Skindersoe, M. E., Phipps, R., Yang, L., Jensen, P.O., Rasmussen, T. B., Bjarnsholt, T., Høiby, N. and Givskov, M. (2008) Effects of antibiotics on quorum sensing in Pseudomonas aeruginosa. Antimicrobial Agents and Chemotherapy 52(10): 3648-3663
• 167. Willcox, M. D. P., Zhu, H., Conibear, T. C. R., Hume, E. B. H., Givskov, M. Kjelleberg, S., Rice, S. A. (2008). Role of quorum sensing by Pseudomonas aeruginosa in microbial keratitis and cystic fibrosis. MICROBIOLOGY 154: 2184-2194
• 168. Kirketerp-Moller, Klaus, Jensen, Peter O., Fazli, Mustafa, Madsen, Kit G., Pedersen, Jette, Moser, Claus, Tolker-Nielsen, Tim, Hoiby, Niels, Givskov, Michael, Bjarnsholt, Thomas (2008) Distribution, organization, and ecology of bacteria in chronic wounds. JOURNAL OF CLINICAL MICROBIOLOGY 46 (8): 2717-2722
• 169. Matz C, Moreno AM, Alhede M, Manefield M, Hauser AR, Givskov M Kjelleberg S (2008) Pseudomonas aeruginosa uses type III secretion system to kill biofilm-associated amoebae. ISME JOURNAL 2 (8): 843-852.
• 170. Claus Moser, Peter Østrup Jensen, Henrik Calum, Thomas Bjarnsholt, Hans Petter Hougen, Michael Givskov, Niels Høiby and Marie Johannesson; Female mice are more susceptible to chronic pseudomonas aeruginosa lung infection; Accapted for publication in APMIS.

Primære forskningsområder

Good health is a key factor of our life and we live with an increasing life expectancy. Despite technological and medical progression, life threatening infections are returning as a serious threat even in well developed countries like Denmark and the societal costs of infectious diseases are considerable. Over the next decades our society will go through changes that greatly affect our sensitivity to microbial pathogens where the most pronounced will be the increase in elderly, immuno-compromised and hospitalized people. Such citizens are susceptible to chronic infections caused by well known bacteria such as Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus. In Denmark, ~100.000 hospitalized patients acquire infections, often in connection with the use of medical devises such as arteriovenous shunts, pacemakers, urinary and other types of catheters, orthopedic devices and mechanical heart valves with an estimated 200-300 annual fatalities. Skin ulcers that develop into chronic wounds are also a significant and partly neglected problem, which affects patients with impaired blood circulation in particular diabetes patients. It is assumed that ~ 50.000 patients suffer from wounds that require special treatment and medical attention because of bacterial infections. This is an important socioeconomic burden, which includes patient suffering, lost employment and reduced life quality. The problem is growing in pace with the increasing emergence of multidrug-resistant bacteria.

In the golden age of antibiotics discovery, potent antibiotics such as penicillin, tetracycline, and vancomycin were discovered and brought to the clinic during the 1940s-1950s. These medicines have saved millions of lives but the backside of the coin is that they by their mode of action (killing the bacteria) strongly promote development of resistant bacterial variants, which rapidly outmatch the original sensitive strains. Infectious diseases that were once treatable with antibiotics will with time become incurable. In order to identify new antimicrobial drug targets, it is imperative to broaden our understanding of the molecular basis of infection, rather than just going in for the kill.

My working hypothesis is the following. The biofilm lifestyle dominates in the above mentioned chronic bacterial infections. Consequently, they share similar characteristics; they tolerate the highest deliverable doses of antibiotics and resist the action of the immune system as well as controlling the infectious process by cell-to-cell communication and internal signal transmission.

Biofilms are agglomerates of microorganisms surrounded by a self-produced extracellular matrix. For example, in the biofilm mode, P. aeruginosa uses "quorum sensing" communication to inform its fellow bacteria that it is time to launch a shield against attaching white blood cells. However, quorum sensing is only the tip of the iceberg of factors governing control over progression of the infectious processes which suggests multiple targets for efficient disease control. In the present project, I intend to generate information about genes at play during infection with particular emphasis on those that are differentially expressed in the biofilm state. Based on this, new anti-biofilm measures can be identified which efficiently decrease the biofilm forming capability or persistence of the infectious bacteria.

So far the majority of biofilm research has been carried out by means of in vitro systems. Much important information regarding gene expression, organization, structural development, antibiotic tolerance and interaction with neutrophiles (PMNs) has been generated this way (see for example refs 95*, 101*, 117*, 124*, 145*). Available data does not support the presence of a unique biofilm program i.e. a collection of genes that is expressed during development and maturation of biofilms (ref 124*).  However, transcending traditional biofilm research into in vivo conditions for example by use of the implant model recently developed by my research team (ref 148*) in combination with transcriptomics will likely promote the discovery new bacterial genes and key proteins. Focus will be on those that are involved in the control mechanisms of the infectious processes. The classical approach is bacterial genetics which employs mutations to perturb the function of gene products. I will also follow a complementary approach, namely "chemical genetics", which uses libraries of natural and synthetic small molecules to perturb expression and function of gene products. My ongoing collaboration with organic and natural products chemists at DTU will provide a diversity of active small molecules, and thereby develop a deeper understanding of the complex biology of bacterial infections.

This in vivo experimental approach will make it possible to identify a collection of infection relevant genes; those that we already are familiar with (for example quorum sensing controlled genes) but importantly, those among the 50% whose function is presently unknown. Selected bacterial genes are then genetically engineered to construct screens for chemical genetics purposes. This will then in turn assists in the identification of bioactive small molecules capable of reducing expression of whole gene collections relevant to infection, in particular those involved in the temporal progression of infection and biofilm tolerance to the immune system.  In other words, by controlling the multiple lines of command, disease-causing bacteria may be disarmed and the biofilms eradicated by the action of the host's defenses. It is important to emphasize that this approach seeks to target genes encoding non-essential phenotypes such as those involved in bacterial adhesion, intercellular signaling (c-di-GMP) and cell to cell signaling (quorum sensing). Blocking those functions does not hamper growth per se and consequently does not create a harsh selection pressure for development of insensitivity as we see with conventional antibiotics.

Chemical genetics approaches are inherently steps closer to drug development than classical genetics; however, it is not the my mission to develop new drugs per se. Small molecule hits may very well have the potential to be drug candidates, but it is naive (and an unrealistic success criterion for university based research funded by public grants) to expect that clinical candidates can be provided. The identification of novel small molecules as powerful tools for biological investigation and proof-of-concept of novel anti-microbial mechanisms (which transcend the past setbacks of resistance/tolerance) defines the meaning of success. At this stage industry must take over (based on shared intellectual properties) and cover the cost of further drug development and clinical trials. Many pharmaceutical companies no longer have antibiotic drugs in the pipeline or, even more worryingly, research activities in the field. The responsibility of uncovering novel antibacterial targets and potent small molecule probes therefore more than ever resides in the academic sector. In addition to creating new and exciting science, these initiatives will also educate a new, strong generation of young scientists, prepared for the multidisciplinary research efforts increasingly demanded by both academia and industry.

My aim is to continuously develop and combine research in molecular infectious biology with chemistry. My ultimate ambition is a paradigm shift in future anti-microbial treatment, fundamentally different from the traditional strategies of directly killing the bacteria with antibiotics, which have prevailed ever since the discovery of penicillin.

What are the structural features of small molecules most likely to yield specific modulation of protein functions involved in the control of infectious processes? It remains difficult to predict which small molecules will best modulate these biological processes and disease states, especially with limited prior knowledge, e.g. protein crystal structures, of the macromolecular targets. It is therefore necessary to systematically screen thousands of small molecules to find a successful match between a chemical and its target. As with the previous screens I have developed (refs 59*, 95*, 117*) for QS regulated gene expression, transcriptomic based analysis mentioned above will provide target genes for construction of those new screens.

Small molecules come in a variety of different shapes, e.g. they may be flat, rod-like, or spherical, and they may contain a variety of atoms with many functions. Natural products are small molecules that tend to be complex, highly three-dimensional in structure, and very different from one to another, whereas compounds made by traditional medicinal chemistry tend to be simple, flat, and alike. Natural products represent a prime source of "chemical diversity", and the hit rates of screening natural product libraries for novel antibiotics by far exceed those of prevalent compound libraries in the pharmaceutical industry. An example of this is my work with garlic (ref 129*). Garlic contains a variety of small molecule chemistry capable of blocking quorum sensing in P. aeruginosa. Previous support from the Strategic Research Council and the German Mukoviszidose  e.V. has enabled us to identify and synthesize QS blocker chemistry and we have used this to successfully treat lung infection in our infectious, pulmonary mouse model.

Much of the medicinal chemistry practiced in industry has failed to provide compounds suitable for antimicrobial drug development, imparted by the strategic mistake of focusing on quantity rather than quality (or chemical diversity). However, given their track record in antimicrobial discovery, there is little reason to assume that natural products could not continue to play an important role in this process. Consequently, in collaboration I will engage in a two-pronged approach for providing novel small molecule libraries for drug discovery: natural products, and synthetic small molecules mimicking the structural features of potent natural products.  "Diversity-oriented synthesis" (DOS) offers the potential to meet structural demands. Unlike traditional strategies for chemical synthesis, the DOS approach enables chemists to rapidly and efficiently synthesize libraries of complex and structurally diverse small molecules in a small number of synthetic steps. Rapid optimization of small molecule properties by structural modification in follow-up studies requires synthetic routes that are as short as possible. Keeping the number of synthetic steps to an absolute minimum ensures that all critical aspects of the small molecule discovery process are met, including optimization, and scale-up.