The broad goal of this project is the design, synthesis, and evaluation of new chemical inducers that modulate cell-cell communication mechanisms in bacteria. The ability of bacteria to communicate with themselves and function as a group is crucial in the development of infectious disease. Gram-negative bacteria use a chemical 'language'of small molecules (or autoinducers) and their cognate protein receptors to sense their local population densities in a phenomenon known as 'quorum sensing'. At high population densities, pathogenic bacteria use this sensing mechanism to organize into structured communities called biofilms and activate virulence pathways that are the basis for myriad chronic infections. The development of methods to control bacterial quorum sensing and attenuate biofilm formation would have a major impact on human health. We hypothesize that synthetic ligands can be used to intercept bacterial autoinducer/ receptor binding and modulate quorum sensing and biofilm formation. This strategy would allow us to address fundamental questions in the field of bacterial communication. First, the ligands we uncover will reveal the molecular level features that are essential for small molecule promotion or suppression of quorum sensing. Second, synthetic ligands could be used to probe the conformational requirements for autoinducer receptor activation and inactivation. Third, tailored higher affinity ligands would enable isolation of the numerous recalcitrant autoinducer receptors. We have developed an approach to address these questions that integrates synthetic organic, combinatorial, and biophysical chemistry techniques to rapidly identify new molecules that modulate quorum sensing in bacteria. The proposed research has three Specific Aims: (1) To design and synthesize new ligands that target bacterial autoinducer receptors, (2) To test the effects of the synthetic ligands on quorum sensing in relevant pathogenic bacteria, and (3) To characterize the binding interactions of non-native ligands with autoinducer receptors using modern biophysical techniques. We have validated this approach in our preliminary studies through the synthesis and identification of a set of new small molecule antagonists of quorum sensing. Relevance: Bacteria use chemical signals to initiate the majority of human infections. The discovery of methods to block these signaling pathways would have a profound impact on public health. There is an urgent, global need for new antimicrobial therapies;the ability to interfere with bacterial virulence by intercepting bacterial communication networks represents a completely new therapeutic approach and is clinically timely.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI063326-05
Application #
7742173
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Korpela, Jukka K
Project Start
2006-01-01
Project End
2012-12-31
Budget Start
2010-01-01
Budget End
2012-12-31
Support Year
5
Fiscal Year
2010
Total Cost
$232,685
Indirect Cost
Name
University of Wisconsin Madison
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Gerdt, Joseph P; Blackwell, Helen E (2014) Competition studies confirm two major barriers that can preclude the spread of resistance to quorum-sensing inhibitors in bacteria. ACS Chem Biol 9:2291-9
Studer, Sarah V; Schwartzman, Julia A; Ho, Jessica S et al. (2014) Non-native acylated homoserine lactones reveal that LuxIR quorum sensing promotes symbiont stability. Environ Microbiol 16:2623-2634
McInnis, Christine E; Blackwell, Helen E (2014) Non-native N-aroyl L-homoserine lactones are potent modulators of the quorum sensing receptor RpaR in Rhodopseudomonas palustris. Chembiochem 15:87-93
Moore, Joseph D; Gerdt, Joseph P; Eibergen, Nora R et al. (2014) Active efflux influences the potency of quorum sensing inhibitors in Pseudomonas aeruginosa. Chembiochem 15:435-42
Broderick, Adam H; Breitbach, Anthony S; Frei, Reto et al. (2013) Surface-mediated release of a small-molecule modulator of bacterial biofilm formation: a non-bactericidal approach to inhibiting biofilm formation in Pseudomonas aeruginosa. Adv Healthc Mater 2:993-1000
Stacy, Danielle M; Le Quement, Sebastian T; Hansen, Casper L et al. (2013) Synthesis and biological evaluation of triazole-containing N-acyl homoserine lactones as quorum sensing modulators. Org Biomol Chem 11:938-54
Crapster, J Aaron; Guzei, Ilia A; Blackwell, Helen E (2013) A peptoid ribbon secondary structure. Angew Chem Int Ed Engl 52:5079-84
Stacy, Danielle M; Welsh, Michael A; Rather, Philip N et al. (2012) Attenuation of quorum sensing in the pathogen Acinetobacter baumannii using non-native N-Acyl homoserine lactones. ACS Chem Biol 7:1719-28
Praneenararat, Thanit; Palmer, Andrew G; Blackwell, Helen E (2012) Chemical methods to interrogate bacterial quorum sensing pathways. Org Biomol Chem 10:8189-99
Frei, Reto; Breitbach, Anthony S; Blackwell, Helen E (2012) 2-Aminobenzimidazole derivatives strongly inhibit and disperse Pseudomonas aeruginosa biofilms. Angew Chem Int Ed Engl 51:5226-9

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