Organic chemistry is in the unique position to provide molecular level insights into biological processes. Renewed appreciation for the power of small molecules as tools to explore living systems has fueled an explosion of interest in chemical biology. Within this broad context, our research program is focused on the development of new synthetic methodology to expedite the discovery of biologically active molecules. We are strategically combining elements of microwave-assisted organic chemistry, solid-phase synthesis, and combinatorial chemistry to provide access to new classes of chemical probes. In turn, we are applying these small molecule tools to bacterial communication and host/microbe interactions, previously unexamined areas of chemical biology. We seek to understand how both plants and animals sense and respond to invasion by pathogenic microbes. The ability of bacteria to communicate with each other and function as a group is a critical step in the development of infectious disease. The reliance of bacteria on a language of small molecules places organic chemists in a unique position to discover the fundamental principles underlying this communication network and design tools to modulate it at the molecular level.
All aspects of our multidisciplinary research program are synergistic with one another. The chemical component drives biological inquiry, and the biological outcomes dictate new avenues for chemical methodology development. Current research projects in our laboratory and their interconnections are outlined below:
We are making contributions in the area of microwave-assisted organic chemistry. Microwave irradiation is seeing increasing use as an alternate heating source for chemical reactions, due to dramatic reductions in reaction times and increases in product yields and purity. We predict that the use of microwave irradiation to expedite solid-phase organic reactions will greatly facilitate the application of combinatorial chemistry to biological problems. We are currently examining the scope and limitations of microwave-assisted solid-phase organic reactions, with particular attention focused on diversity-generating reactions that do not proceed at an appreciable rate under standard thermal conditions, e.g., selected multicomponent, cyclization, and condensation reactions. We have recently used this methodology to synthesize new classes of peptidomimetics (i.e., peptoids).
Our methodological work is enabling us to develop a powerful and accessible solid-phase synthesis platform for the rapid generation of focused, small molecule libraries. We have engineered a synthesis platform that allows modest sized (100-500 member) libraries to be prepared routinely in one day. The platform consists of functionalized planar polymeric supports and library synthesis is performed in a spatially addressable manner to generate small molecule macroarrays. The application of microwave irradiation (see above) to selected reactions during macroarray construction permits diverse chemical libraries to be generated at unprecedented rates. The use of our synthesis platform is accelerating the pace at which new biologically active compounds are discovered (see below).
With the development of our synthesis platform well underway, we are designing, preparing, and screening focused collections of small molecules to ask important questions in bacteriology. Specifically, we seek to uncover compounds that modulate key protein-protein interactions involved in bacterial communication pathways. At present, we are trying to intercept the binding of bacterial LuxR-type proteins to their cognate autoinducer ligands and subsequent homodimerization, which are pivotal events in Gram-negative bacterial quorum sensing circuits. Compounds uncovered in these screens will be the first to reveal molecular level features essential for autoinducer-regulated quorum sensing. Quorum sensing regulated behaviors in bacteria account for greater than 50% of all crop disease and 80% of human infections, therefore, active compounds emerging from our research could serve as scaffolds for agricultural agents and therapeutics with unprecedented modes of action. Our unique ability to rapidly manipulate the chemical structures of these molecules using microwave-assisted reactions will streamline their development as powerful tools in the laboratory, in the clinic, and in the field. Using this approach, we recently identified a set of quorum sensing antagonists that are among the most potent reported to date. On-going work is focused on further developing these compounds as probes, designing the first quorum sensing "super agonists", and applying our integrated research approach to examine the alternate quorum sensing pathways used by Gram-positive bacterial pathogens.