CRYSTALLOGRAPHIC STUDIES OF ANTIBIOTIC RESISTANCE PROTEINS AND SIGNAL TRANSDUCTI

Stanford University, Stanford CA

Investigators

Linked publications, trials & patents

Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The development of antibiotic resistance to bacterial infections is a serious human threat in large part due to bacterial beta-lactamases. Inhibition of these beta-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 beta-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. Dr. Buynak has synthesized close to 100 different inhibitors within 1 year which increases the scope of this crystallographic project substantially. In addition, our lab focuses on structural studies of cyclic nucleotide signaling. We have solved the structure of a heme domain homologous that the H-NOX domain in the soluble guanylyl cyclase (sGC), a key drug target for heart failure. This heme domain is the target of heme-mimetic drug candidates and we recently have solved the structure of this H-NOX domain in complex with the BAY 58-2667 activator being the first crystal structure of a heme-mimetic. Additional activator:H-NOX complex structures are targeting in this proposal to obtain key insights into the functioning of these compounds. This latter project is aimed to providing structural insights into cyclic nucleotide signaling pathways involving in blood pressure reg