Like S typhimurium, V harveyi is responsive to the AI-2 class of autoinducers. The second screen capitalized on the inability of V harveyi cells to luminesce through either the AHL pathway or the AI-2 pathway in the absence of exogenous DPD. Application of the DPD analogs to V harveyi cultures resulted in only mild agonist activity. However, addition of 1 μ M DPD to these cultures had a dramatic synergistic effect: activation of bioluminescence with the DPD analogs was several-fold greater than that caused by 1 μ M DPD alone (Fig. 1B).
Impeding Bacterial Infection Through Antibodies Against Quorum-Sensing Compounds
We have pioneered an antibody-based strategy
to combat bacterial infectivity by disrupting transmission of quorum-sensing signals.
Recently, we applied our antibody-based technology to disruption of the quorum-sensing
circuits of Pseudomonas aeruginosa. This gram-negative bacterium uses various
quorum-sensing systems for more nefarious purposes with respect to interspecies
communication. Namely, the 2-alkyl-4-quinolones and related AHLs (Fig. 2) secreted
by P aeruginosa have antibacterial activity against gram-positive bacteria,
allowing P aeruginosa to outcompete other bacterial species within a shared
environment. The clinical relevance of quorum sensing by P aeruginosa includes
the displacement of Staphylococcus aureus in the lungs of patients with cystic fibrosis and detrimental
AHL-mediated immunomodulation in host cells, including an altered inflammatory response,
a weakened host defense system, and induction of apoptosis. Therefore, removal of
AHLs, which are thought to mediate the cytotoxicity in mammalian macrophages and
neutrophils, may be advantageous to controlling this aspect of quorum sensing–related
To this end, we engineered monoclonal antibodies against AHL targets, and most notably, we showed that the monoclonal antibody RS2-1G9 had inhibitory activity in vitro against quorum sensing of P aeruginosa based on 3-oxo-C12-homoserine lactone (3-oxo-C12-HSL; Fig. 2). RS2-1G9 not only protected murine macrophages exposed to 3-oxo-C12-HSL in a concentration-dependent manner but also prevented the downstream activation of cellular stress kinase pathways, indicating complete sequestration of 3-oxo-C12-HSL. Thus, using this immunopharmacotherapy to quench expression of bacterial virulence factors and quorum sensing holds promise both in preventing infection and AHL-associated cytotoxicity and in developing therapies that will not promote the evolution of methicillin-resistant S aureus and future "superbugs."
Brogan, A.P., Dickerson, T.J., Janda, K.D. Nornicotine-organocatalyzed aqueous reduction of α,β-unsaturated aldehydes. Chem. Commun. (Camb.) Issue 46:4952, 2007.
Capková, K., Hixon, M.S., McAllister, L.A., Janda, K.D. Toward the discovery of potent inhibitors of botulinum neurotoxin A: development of a robust LC MS based assay operational from low to subnanomolar enzyme concentrations. Chem. Commun. (Camb.) Issue 30:3525, 2008.
Capková, K., Yoneda, Y., Dickerson, T.J., Janda, K.D. Synthesis and structure-activity relationships of second-generation hydroxamate botulinum neurotoxin A protease inhibitors. Bioorg. Med. Chem. Lett. 17:6463, 2007.
Debler, E.W., Kaufmann, G.F., Meijler, M.M., Heine, A., Mee, J.M., Pljevaljcic, G., Di Bilio, A.J., Schultz, P.G., Millar, D.P., Janda, K.D., Wilson, I.A., Gray, H.B., Lerner, R.A. Deeply inverted electron-hole recombination in a luminescent antibody-stilbene complex. Science 319:1232, 2008.
Kaufmann, G.F., Park, J., Janda, K.D. Bacterial quorum sensing: a new target for anti-infective immunotherapy. Expert Opin. Biol. Ther. 8:719, 2008.
Kaufmann, G.F., Park, J., Mee, J.M., Ulevitch, R.J., Janda, K.D. The quorum quenching antibody RS2-1G9 protects macrophages from the cytotoxic effects of the Pseudomonas aeruginosa quorum sensing signalling molecule N-3-oxo-dodecanoyl-homoserine lactone. Mol. Immunol. 45:2710, 2008.
Kravchenko, V.V., Kaufmann, G.F., Mathison, J.C., Scott, D.A., Katz, A.Z., Grauer D.C., Lehmann, M., Meijler, M.M., Janda, K.D., Ulevitch, R.J. Modulation of gene expression via disruption of NF-κB signaling by a bacterial small molecule. Science 321:259, 2008.
Lowery, C.A., Dickerson, T.J., Janda, K.D. Interspecies and interkingdom communication mediated by bacterial quorum sensing. Chem. Soc. Rev. 37:1337, 2008.
Lowery, C.A., Park, J., Kaufmann, G.F., Janda, K.D. An unexpected switch in the modulation of AI-2-based quorum sensing discovered through synthetic 4,5-dihydroxy-2,3-pentanedione analogues. J. Am. Chem. Soc. 130:9200, 2008.
Park, J., Dickerson, T.J., Janda, K.D. Major sperm protein as a diagnostic antigen for onchocerciasis. Bioorg. Med. Chem. 16:7206, 2008.
Park, J., Jagasia, R., Kaufmann, G.F., Mathison, J.C., Ruiz, D.I., Moss, J.A., Meijler, M.M., Ulevitch, R.J., Janda, K.D. Infection control by antibody disruption of bacterial quorum sensing signaling. Chem. Biol. 14:1119, 2007.
Park, J., Kaufmann, G.F., Bowen, J.P., Arbiser, J.L., Janda K.D. Solenopsin A, a venom alkaloid from the fire ant Solenopsis invicta, inhibits quorum sensing signaling in Pseudomonas aeruginosa. J. Infect. Dis. 198:198, 2008.
Richardson, H.N., Zhao, Y., Fekete, E.M., Funk, C.K., Wirsching, P., Janda, K.D., Zorrilla, E.P., Koob, G.F. MPZP: a novel small molecule corticotropin-releasing factor type 1 receptor (CRF1) antagonist. Pharmacol. Biochem. Behav. 88:497, 2008.
Willis, B., Eubanks, L.M., Dickerson, T.J., Janda, K.D. The strange case of the botulinum neurotoxin: using chemistry and biology to modulate the most deadly poison. Angew. Chem. Int. Ed.47:8360, 2008.
Willis, B., Eubanks, L.M., Wood, M.R., Janda, K.D., Dickerson, T.J., Lerner, R.A. Biologically templated organic polymers with nanoscale order. Proc. Natl. Acad. Sci. U. S. A. 105:1416, 2008.
Xu, Y., Hixon, M.S., Dawson, P.E., Janda, K.D. Development of a FRET assay for monitoring of HIV gp41 core disruption. J. Org. Chem. 72:6700, 2007.
Yoneda, Y., Steiniger, S.C., Capková, K., Mee, J.M., Liu, Y., Kaufmann, G.F., Janda, K.D. A cell-penetrating peptidic GRP78 ligand for tumor cell-specific prodrug therapy. Bioorg. Med. Chem. Lett. 18:1632, 2008.
Zarebski, L.M., Vaughan, K., Sidney, J., Peters, B., Grey, H., Janda, K.D., Casadevall, A., Sette, A. Analysis of epitope information related to Bacillus anthracis and Clostridium botulinum. Expert Rev. Vaccines 7:55, 2008.
Zhou, B., Carney, C., Janda, K.D. Selection and characterization of human antibodies neutralizing Bacillus anthracis toxin. Bioorg. Med. Chem. 16:1903, 2008.
Zhou, B., Pellett, S., Tepp, W.H., Zhou, H., Johnson, E.A., Janda, K.D. Delineating the susceptibility of botulinum neurotoxins to denaturation through thermal effects. FEBS Lett. 582:1526, 2008.
Zhou, H., Zhou, B., Ma, H., Carney, C., Janda, K.D. Selection and characterization of human monoclonal antibodies against Abrin by phage display. Bioorg. Med. Chem. Lett. 17:5690, 2007.