This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The development of antibiotic resistance to bacterial infections is a serious human threat in large part due to bacterial b-lactamases. Inhibition of these b-lactamases is therefore a key pharmaceutical approach. Our lab focuses on delineating the molecular inhibition mechanism of clinically available inhibitors, additional potent inhibitors that are in, or close to, clinical trials, and our own designed inhibitors. The inhibition mechanism is complex involving a large number of covalent intermediates that we study using a novel X-ray and Raman crystallographic approach. High resolution crystallographic studies are proposed for inhibitor complexes for a variety of different clinically relevant b-lactamases classes including KPC-2, recently linked to an K. pneumoniae outbreak in New York, SHV-1, and OXA-1, OXA-10, and OXA-24/40. Both OXA24/40 and KPC-2 are a major threat to carbapenems, a last resort antibiotic. Our inhibitors are developed in collaboration with Dr. Buynak (Southern Methodist University) and are designed to form a stable inhibitory intermediate, either by forming a trans-enamine or bicyclic aromatic ring intermediate. In addition, we are embarking on using fragment-mixture soaked b-lactamase crystals as a tool for finding new lead compounds. In addition, our lab focuses on structural studies of cyclic nucleotide signaling. We have recently crystallized the coiled-coil domain of a guanylyl cyclase involved in blood pressure regulation. Crystals diffract to 2? and we plan on collecting a SeMet MAD dataset. Finally, we have crystallized several cyclic nucleotide binding domains of ion channels of which we determined the structure of one, and have diffracting crystals for two others. The latter project is aimed to providing structural insights into cyclic nucleotide signaling pathways involving in blood pressure regulation, bone growth and other important physiological processes.
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