Quorum sensing (QS) allows many common bacterial pathogens to coordinate group behaviors such as virulence factor production, host colonization, and biofilm formation at high population densities. This cell–cell signaling process is regulated by N-acyl L-homoserine lactone (AHL) signals, or autoinducers, and LuxR-type receptors in Gram-negative bacteria. SdiA is an orphan LuxR-type receptor found in Escherichia, Salmonella, Klebsiella, and Enterobacter genera that responds to AHL signals produced by other species and regulates genes involved in several aspects of host colonization. The inhibition of QS using non-native small molecules that target LuxR-type receptors offers a non-biocidal approach for studying, and potentially controlling, virulence in these bacteria. To date, few studies have characterized the features of AHLs and other small molecules capable of SdiA agonism, and no SdiA antagonists have been reported.
Chemical strategies to block quorum sensing (QS) could provide a route to attenuate virulence in bacterial pathogens. Considerable research has focused on this approach in Pseudomonas aeruginosa, which uses the LuxR-type receptor LasR to regulate much of its QS network. Non-native ligands that antagonize LasR have been developed, yet we have little understanding of the mode by which these compounds interact with LasR and alter its function, as the receptor is unstable in their presence. Herein, we report an approach to circumvent this challenge through the study of a series of synthetic LasR agonists with varying levels of potency. Structural investigations of these ligands with the LasR ligand-binding domain reveal that certain agonists can enforce a conformation that deviates from that observed for other, often more potent agonists. These results, when combined with cell-based and biophysical analyses, suggest a functional model for LasR that could guide future ligand design.
The research group of GME lab is focused on the combination of advances in molecular biology, genomics and bioinformatics with the powerful techniques of modern epidemiology and statistics to characterize epigenetic states in human health and diseases.
We study a diverse set of diseases from diabetes mellitus to autism by incorporating both molecular and environmental influences into our studies. Our molecular data spans various omics categories from whole genome genotype and sequence data to transcriptome data to understand the molecular influence and underlying biology of disease.
In addition, our research group also focused on understanding the molecular epidemiology of important multidrug resistant (MDR) food borne pathogens at the pre-harvest and post-harvest food safety levels. Our specific goal is to determine the dynamics of MDR bacteria in poultry, retail meat, humans and the environment. With this information, we plan to achieve our long term goal of reducing the burden of infections caused by bacterial pathogens in food animals and humans.