In my lab we've been working on a new concept in reducing the harm caused by bacterial infections. Many bacteria have a system for determining their own population density. They do this by excreting into their surroundings a low molecular weight compound (a bacterial pheromone, really). When the concentration of this compound reaches a critical level, the bacteria sense that there is a "quorum," and then start doing a new thing. This was originally discovered in the bioluminescent bacteria where the new thing is light production. In pathogenic bacteria, the new thing is to invade the organism. For instance, patients with cystic fibrosis or immune-compromised patients, such as those with AIDS or people getting transplants or the elderly, can get their lungs infected with the bacterium Pseudomonas aeruginosa. As such, that's not too bad and just produces slime and a lot of coughing. But if the bacteria sense that there's enough of them (which they do by means of these low molecular weight compounds) they turn on the genes for making the enzymes to dissolve the lung tissue. Then they're in the blood stream and the patient is history.
We've determined the structure of these low molecular weight compounds (called "autoinducers") and are now working on several fronts: 1) we're making analogs of the autoinducers in the hope of finding an inhibitor that will block the bacteria's response to the natural autoinducers. Then, no matter how many bacteria there are, they will think they are alone and will not invade the bloodstream. Note that we plan not to kill the bacteria, but just to keep them from doing bad things. That way they shouldnot be able to get resistant to our analogs, while with the usual killing antibiotics, resistance develops rapidly; 2) we (and a lot of other people) are analyzing various other bacteria to see whether they have autoinducers, and if so, what they are. For instance, we're working on a strain that is used widely for bioremediation (eating up oil spills) and another one that infects plants to make crown gall tumors. We've found that these bacteria often produce several slightly different autoinducers. A hot topic is to find out what all these autoinducers are and to determine what genes each of them is controlling.
In our research, the students routinely use our excellent instrumentation, such as high performance liquid chromatography (HPLC); ultraviolet (uv), infrared (ir) and fluorescence spectrophotometry; gas-liquid chromatography (glc), gas-chromatography-mass spectrometry (GC-MS), nuclear magnetic resonance (nmr), and luminometry. The students also grow the bacteria and test the effects of the compounds we make on the bacteria. Our work with students and collaborators has resulted in several published papers and in papers presented at meetings: C.P. Channing; A. Eberhard; A.H. Guindon; V. Massey and C. Veegar (1962) "Purification and Some Properties of Lipoyl Dehydrogenase from Dogfish Liver," Biol. Bull. 123, 480 (Abstract).A. Eberhard and F.H. Westheimer (1965) "Hydrolysis of Phostonates," J. Amer. Chem. Soc. 87, 253.
A. Eberhard and D. Mazia (1965) "Conditions for Extraction of Cytoplasmic DNA from Embryos of a Sea Urchin," Biochem. Biophys. Res. Commun. 21, 460.
J.W. Hastings; K. Weber; J. Friedland; A. Eberhard; G.W. Mitchell and A. Gunsalus (1969) "Structurally Distinct Bacterial Luciferases," Biochemistry 8, 4681.
A. Eberhard and G. Rouser (1971) "Quantitative Analysis of the Phospholipids of Some Marine Bioluminescent Bacteria," Lipids 6, 410 .
A. Eberhard (1972) "Pattern of Dissolution of Deoxyribonucleic Acid in Trichloroacetic Acid in the Presence of Protein," Anal. Biochem. 46, 660 .
A. Eberhard (1972) "Inhibition and Activation of Bacterial Luciferase Synthesis," J. Bacteriol. 109, 1101 .
K.H. Nealson; A. Eberhard and J.W. Hastings (1972) "Catabolite Repression of Bacterial Bioluminescence: Functional Implications, "Proc. Nat. Acad. Sci. USA 69, 1073.
A. Eberhard and J.W. Hastings (1972) "A Postulated Mechanism for the Bioluminescent Oxidation of Reduced Flavin Mononucleotide," Biochem. Biophys. Res. Commun.47, 348.
A. Eberhard (1972) "Long Term Survival of Bioluminescent Bacteria in Sea Water," Biol. Bull. 143, 459 (Abstract).
J. Magner; A. Eberhard and K.H. Nealson (1972) "Characterization of Bioluminescent Bacteria by Studies of Their Inducers of Luciferase Synthesis," Biol. Bull.143, 469 (Abstract).
A. Eberhard; D. Bentley and R. Solsky (1973) "Aldehyde Analogs and the Mechanism of Bacterial Bioluminescence," Biol. Bull. 145, 432 (Abstract)
J.W. Hastings; A. Eberhard; T.O. Baldwin; M.Z. Nicoli; T.W. Cline and K.H. Nealson (1973) "Bacterial Bioluminescence. Mechanistic Implications of Active Center
Chemistry of Luciferase," in Chemiluminescence and Bioluminescence M.J. Cormier; D.M. Hercules, J. Lee, eds., Plenum Pub. Corp., N.Y., pp. 369-380.
D. Bentley; A. Eberhard and R. Solsky (1974) "Decyl Nitrite: An Aldehyde Analog in the Bacterial Bioluminescence Reaction," Biochem. Biophys. Res. Commun. 56, 865.
A. Eberhard (1974) "Anaerobic Synthesis of Bacterial Luciferase," Biol. Bull. 147, 475 (Abstract).
A. Eberhard; J.P. Hinton and R.M. Zuck (1979) "Luminous Bacteria Synthesize Luciferase Anaerobically," Arch. Microbiol. 121, 277.
A. Eberhard; A. Burlingame; C. Eberhard; G.L. Kenyon; and N.J. Oppenheimer (1980) "Isolation and Identification of the Autoinducer of Photobacterium fischeri Luciferase," Annu. Meeting, Amer. Soc. Microbiol. 154 (K164) (Abstract).
A. Eberhard; A.L. Burlingame; C. Eberhard; G.L. Kenyon; K.H. Nealson; and N.J. Oppenheimer (1981) "Structural Identification of the Autoinducer of Photobacterium fischeri Luciferase," Biochemistry 20, 2644.
A. Eberhard; C. Eberhard; A.L. Burlingame; G.L. Kenyon and N.J. Oppenheimer (1981)
"Purification, Identification and Synthesis of Photobacterium fischeri Autoinducer," in "A Symposium on Bioluminescence and Chemiluminescence," (M. DeLuca and W.D. McElroy, ed.), 113-120, Academic: New York, N.Y.
H.B. Kaplan; E.P. Greenberg; A. Eberhard and C. Widrig (1984) "Autoinduction of Luminescence in Vibrio fischeri: Use of Radiolabeled Inducer in Mechanistic Studies." 84th Annual Meeting of the Am. Soc. for Microbiol. 137 (Abstract).
H.B. Kaplan; A. Eberhard; C. Widrig and E.P. Greenberg (1985) "Synthesis of N-[3-oxo-(4.5-3H2)-hexanoyl]homoserine lactone: Biologically active tritium-labelled Vibrio fischeri autoinducer," J. Labelled Cmpds Radiopharm. 22, 387-395.
A. Eberhard; C.A. Widrig; Paula McBath; and J.B. Schineller (1986) "Analogs of the autoinducer of bioluminescence in Vibrio fischeri," Arch Microbiol. 146, 35-40.
A. Eberhard (1986) "Anaerobic fluorescence titration of dithionite solutions," Analyst. 111, 475-476.
A. Eberhard and G.L. Kenyon (1987) "Tungstate analysis using an iron salt, a thiol and oxygen," Analyst 112, 305-307.
A. Eberhard (1987) "Using HPLC to De-salt and Concentrate Biochemicals," Chromatogram 8 (2), 10.
S.M. Merkel; A. Eberhard; J. Gibson and G.S. Harwood (1989) "Involvement of Coenzyme A Thioesters in Anaerobic Metabolism of 4-Hydrozybenzoate by Rhodopseudomonas palustris," J. Bact. 171, 1-7.
A. Eberhard; S.J. Stranick and J. MacNeil (1991) "Solvent-delivery and helium-sparging System for High Performance Liquid Chromatography," LC-GC 9, 132-134.
M. Ahrens; P. Macheroux; A. Eberhard; S. Ghisla; B.P. Branchaud and J.W. Hastings (1991) "Boronic acids as mechanistic probes for the bacterial luciferase reaction," Photochem. Photobiol. 54, 295-299.
A. Eberhard; T. Longin; C.A. Widrig and S.J. Stranick (1991)"Synthesis of the lux gene autoinducer in Vibrio fischeri is positively autoregulated," Arch. Microbiol. 155, 294-297.
J.P. Pearson; K.M. Gray; L. Passador; K.D. Tucker; A. Eberhard; B.H. Iglewski and E.P.Greenberg (1993) "Structure of the autoinducer required for expression of Pseudomonas aeruginosa virulence genes," Seventh Annual North American Cystic Fibrosis Conference, Dallas, TX, Oct. 13-16, pg. 257 (Abstract).
J.P. Pearson; K.M. Gray; L. Passador; K.D. Tucker; A. Eberhard; B.H. Iglewski and E.P.Greenberg (1994) "Structure of the autoinducer required for expression of Pseudomonas aeruginosa virulence genes," Proc. Natl. Acad. Sci. USA 91, 197-201.
A. Eberhard and C. Warnokowski (1993) "Rate of decomposition of Vibrio fischeri autoinducer," Bioluminescence Symposium, Maui, Hawaii, Nov. 5-10, No. PO87, p. 94 (Abstract).
Schaefer, A.L.; Hanzelka, B.L.; Eberhard, A.; and Greenberg, E.P. (1996) "Quorum Sensing in Vibrio fischeri: Probing Autoinducer-LuxR Interactions with Autoinducer Analogs." J. Bacteriol. 178, 2897-2901.
Moré, M.I.; Finger, L.D.; Stryker, J.D.; Fuqua, C.; Eberhard, A. and Winans, S.C. (1996) "Enzymatic Synthesis of a Quorum-sensing Autoinducer Through Use of Defined Substrates." Science 272, 1655-1658.
Zhu, J.; J.W. Beaber; M.I. Moré; C. Fuqua; A. Eberhard and S.C. Winans (1998) "Analogs of the autoinducer 3-oxooctanoyl-homoserine lactone strongly inhibit activity of the TraR protein of Agrobacterium tumefaciens , J. Bacteriol. 180, 5398-5405.
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