Interrupting quorum sensing and cyclic dinucleotide signaling in bacteria and immune cells with small molecules
The ability of cells to sense and respond to environmental cues is critical for survival. Bacteria utilize quorum sensing molecules and nucleotide-based second messengers to regulate a myriad of physiological processes. Quorum sensing molecules are secreted by bacteria and are involved in cell-to-cell (both bacteria-to-bacteria and bacteria-to-host) communications. Cells integrate quorum sensing and environmental cues to regulate the synthesis and degradation of cyclic dinucleotides such as c-di-GMP, c-di-AMP and cGAMP (3'3'-). In Gram-negative, Gram-positive bacteria and mycobacteria, cyclic dinucleotides orchestrate a dizzying array of processes that include biofilm formation, virulence factors production, cell wall remodeling and antibiotic resistance. Cyclic dinucleotides also affect mammalian cells, particularly immune cells. For example, c-di-AMP secreted by the intracellular pathogen L. monocytogenes into the cytosol of the host immune cells elicits a robust host type 1 interferon response in a STING-dependent manner. Furthermore, Type 1 interferon response is also induced by the host-derived cyclic dinucleotide, cGAMP (2'3'-), produced by a human cyclic dinucleotide synthase called cGAS. The central roles played by quorum sensing/cyclic dinucleotide signaling cascades make these systems prime drug targets. Host proteins that interact with bacteria signaling molecules could be targets for potentiating immune response to bacteria or damping down inflammation. Thus far very few host proteins that bind to quorum sensing molecules and/or cyclic dinucleotides have been characterized. Also there is a paucity of small molecule inhibitors that disrupt cyclic dinucleotide signaling in bacteria or immune cells. The Sintim group is interested in the identification of key players that mediate bacteria-host interactions. We are also interested in developing small molecules to interrupt cell-to-cell communication in both bacteria and higher organisms. Such inhibitors of cell-to-cell communication have wide applications, ranging from anti-virulence/anti-biofilm agents to anti-inflammatory/anti-cancer agents.