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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI080715-05
Application #
8416430
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Xu, Zuoyu
Project Start
2009-02-12
Project End
2014-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
5
Fiscal Year
2013
Total Cost
$437,385
Indirect Cost
$207,061
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Garner, Amanda L; Kim, Sook Kyung; Zhu, Jie et al. (2012) Stereochemical insignificance discovered in Acinetobacter baumannii quorum sensing. PLoS One 7:e37102
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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

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