Quorum sensing (QS) is widespread in bacteria and plays a pivotal role in their interactions with eukaryotic hosts. This intercellular signaling mechanism is based on small molecule ligands and their cognate protein receptors, and allows bacteria to assess their local population densities and function as a group. The long-term objective of the proposed research is to design, synthesize, and characterize non-native small molecules capable of intercepting native QS signals for use as tools to dissect the myriad roles of QS in bacterial populations and in bacteria-host associations. The potential impact of such chemical probes is enormous, and ranges from applications in basic research to therapeutic and biomaterials development. As many of the most notorious human pathogens use QS to activate virulence pathways that are the origin of acute and chronic infections, including biofilm formation, the application of QS antagonists holds significant promise as a novel antimicrobial strategy. Such "anti-virulence" agents differ from current antibiotics because they target infectivity as opposed to growth, and represent a paradigm shift for the treatment of bacteria-mediated disease. QS in Gram-negative bacteria is the best characterized to date and the focus of this project. These QS circuits are based on N-acyl L-homoserine lactone (AHL) signals and LuxR-type transcription factors, and binding of the AHL to its target LuxR-type receptor triggers QS-controlled gene expression at high cell densities. In earlier work, we studied the structures of LuxR-type receptor ligand-binding sites, designed non-native ligands capable of targeting these sites, and developed efficient synthetic routes to libraries of these compounds. Evaluation of the libraries in model bacterial strains revealed several of the most potent synthetic antagonists and agonists of LuxR-type QS reported to date. These results validate our overall research strategy. Our intent now is to develop new small molecules scaffolds capable of intercepting LuxR-type QS with improved potencies and stabilities, determine the mechanisms by which these compounds exert their QS modulatory activities, and examine their ability to attenuate QS phenotypes in wild-type human pathogens. During the grant period, these objectives will be pursued in three Specific Aims. These are: (1) Design and Structural Optimization of New Synthetic QS Antagonists and Agonists, (2) Mechanistic Analysis of LuxR-type Receptor Antagonism and Agonism by Synthetic Ligands, and (3) Cell-Based Virulence Assays and Studies of Resistance Development to QS Antagonists. The results of the interdisciplinary research proposed herein will provide fundamental insights into the mechanisms of QS and ultimately could provide an approach for the development of next- generation, anti-virulence treatments for bacterial infection.
Bacteria use chemical signals to communicate with each other and initiate human infections at high cell densities. 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 new therapeutic approach and is clinically timely.
|O'Reilly, Matthew C; Blackwell, Helen E (2016) Structure-Based Design and Biological Evaluation of Triphenyl Scaffold-Based Hybrid Compounds as Hydrolytically Stable Modulators of a LuxR-Type Quorum Sensing Receptor. ACS Infect Dis 2:32-38|
|Yang, Tian; Tal-Gan, Yftah; Paharik, Alexandra E et al. (2016) Structure-Function Analyses of a Staphylococcus epidermidis Autoinducing Peptide Reveals Motifs Critical for AgrC-type Receptor Modulation. ACS Chem Biol 11:1982-91|
|Welsh, Michael A; Blackwell, Helen E (2016) Chemical Genetics Reveals Environment-Specific Roles for Quorum Sensing Circuits in Pseudomonas aeruginosa. Cell Chem Biol 23:361-9|
|Welsh, Michael A; Blackwell, Helen E (2016) Chemical probes of quorum sensing: from compound development to biological discovery. FEMS Microbiol Rev 40:774-94|
|Moore, Joseph D; Rossi, Francis M; Welsh, Michael A et al. (2015) A Comparative Analysis of Synthetic Quorum Sensing Modulators in Pseudomonas aeruginosa: New Insights into Mechanism, Active Efflux Susceptibility, Phenotypic Response, and Next-Generation Ligand Design. J Am Chem Soc 137:14626-39|
|Welsh, Michael A; Eibergen, Nora R; Moore, Joseph D et al. (2015) Small molecule disruption of quorum sensing cross-regulation in pseudomonas aeruginosa causes major and unexpected alterations to virulence phenotypes. J Am Chem Soc 137:1510-9|
|Gerdt, Joseph P; McInnis, Christine E; Schell, Trevor L et al. (2015) Unraveling the contributions of hydrogen-bonding interactions to the activity of native and non-native ligands in the quorum-sensing receptor LasR. Org Biomol Chem 13:1453-62|
|Eibergen, Nora R; Moore, Joseph D; Mattmann, Margrith E et al. (2015) Potent and Selective Modulation of the RhlR Quorum Sensing Receptor by Using Non-native Ligands: An Emerging Target for Virulence Control in Pseudomonas aeruginosa. Chembiochem 16:2348-56|
|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|
|Gerdt, Joseph P; McInnis, Christine E; Schell, Trevor L et al. (2014) Mutational analysis of the quorum-sensing receptor LasR reveals interactions that govern activation and inhibition by nonlactone ligands. Chem Biol 21:1361-9|
Showing the most recent 10 out of 13 publications