The initial discovery that Gram-negative bacteria, such as Vibrio fischeri and Pseudomonas aeruginosa, employ small diffusible molecules, namely N-acyl homoserine lactones, to globally regulate the production of secondary metabolites and proteins, initiated a new area in microbiological research, the field of quorum sensing. Subsequently, other quorum sensing systems and signaling molecules have been identified, including oligopeptides in Gram-positive bacteria, such as Staphylococcus aureus. Quorum sensing systems seem to be evolutionary conserved and many of them are involved in the control of bacterial pathogenesis. With the emergence of more highly antibiotic-resistant bacterial strains ("superbugs"), most notably methicillin-resistant S. aureus (MRSA) and P. aeruginosa, new approaches for combating bacterial infections are desperately needed. In fact, the Center for Disease Control and Prevention (CDC) has estimated that 94,000 invasive MRSA infections occurred in the U.S in 2005 and more than 19,000 Americans died from these infections - more than annual HIV/AIDS casualties. Bacterial quorum sensing signaling molecules might represent such new targets for anti-infective immunotherapy. The powerful combination of chemistry and molecular biology will be harnessed to provide a solid rational basis for quorum quenching therapeutic agents.
The specific aims of our R01 application are: (1) Therapeutic targeting of AHL-based Quorum Sensing in Pseudomonas aeruginosa;and (2) The agr Quorum Sensing System in Staphylococcus aureus as target for Immunotherapy.

Public Health Relevance

Bacterial pathogens, even so-called antibiotic-resistant "super bugs", utilize cell-to-cell signaling, a process termed "quorum sensing", to control their virulence. The molecules that bacteria use for their communication represent attractive targets for anti-infective therapy as the scavenging of the small compounds would render the bacteria harmless. We propose to develop antibodies and harness the immune system in general for the disruption of bacterial quorum sensing and thus, a new strategy in fighting bacterial infections.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Xu, Zuoyu
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Scripps Research Institute
La Jolla
United States
Zip Code
Struss, Anjali K; Nunes, Ashlee; Waalen, Jill et al. (2013) Toward implementation of quorum sensing autoinducers as biomarkers for infectious disease states. Anal Chem 85:3355-62
Kravchenko, Vladimir V; Gloeckner, Christian; Stowe, G Neil et al. (2012) The use of small molecule probes to study spatially separated stimulus-induced signaling pathways. Bioorg Med Chem Lett 22:2043-5
Rumbaugh, Kendra P; Kaufmann, Gunnar F (2012) Exploitation of host signaling pathways by microbial quorum sensing signals. Curr Opin Microbiol 15:162-8
Kravchenko, Vladimir V; Ulevitch, Richard J; Kaufmann, Gunnar F (2011) Modulation of mammalian cell processes by bacterial quorum sensing molecules. Methods Mol Biol 692:133-45
Lowery, Colin A; Kaufmann, Gunnar F; Janda, Kim D (2011) Determination of acyl homoserine lactone and tetramic acid concentrations in biological samples. Methods Mol Biol 692:101-11
Amara, Neri; Krom, Bastiaan P; Kaufmann, Gunnar F et al. (2011) Macromolecular inhibition of quorum sensing: enzymes, antibodies, and beyond. Chem Rev 111:195-208
Kaufmann, Gunnar F; Park, Junguk; Mayorov, Alexander V et al. (2011) Generation of quorum quenching antibodies. Methods Mol Biol 692:299-311
Kirchdoerfer, Robert N; Garner, Amanda L; Flack, Caralyn E et al. (2011) Structural basis for ligand recognition and discrimination of a quorum-quenching antibody. J Biol Chem 286:17351-8
Garner, Amanda L; Park, Junguk; Zakhari, Joseph S et al. (2011) A multivalent probe for AI-2 quorum-sensing receptors. J Am Chem Soc 133:15934-7
Lowery, Colin A; Salzameda, Nicholas T; Sawada, Daisuke et al. (2010) Medicinal chemistry as a conduit for the modulation of quorum sensing. J Med Chem 53:7467-89

Showing the most recent 10 out of 11 publications