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 threats and in large part to bacterial -lactamases. A powerful solution for treating infections is the co-administration of a -lactamase inhibitor (such as tazobactam, sulbactam, and clavulanic acid) to which unfortunately resistance has emerged. Our proposal is focused on delineating at an atomic level the inhibitor resistance of the novel -lactamase variants. Our novel approach to trap reaction intermediates is to use in-house Raman crystallography to pre-characterize the inhibitor soaked crystals and determine the type of intermediate as well as the population of this intermediate with respect to time which resulted in three crystal structures of such complexes (Padayatti et al., JBC 2004 & 2005). Current efforts are to focus on inhibitor resistance variants of SHV beta-lactamase, complexes with novel designed inhibitors. High and ultra-high resolution structures are needed to investigate the subtle conformational changes that are expected as well as locate hydrogens that are part of the reaction mechanism. In addition, we have crystallized 4 different cyclic nucleotide binding domains from bacteria that show a significant homology with that of ion channels.
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