This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.he protection Beta-lactam antibiotics afford humans against infection is being eroded by the increasing prevalence of bacteria containing AmpC beta-lactamases. These enzymes destroy a range of our most safe and effective antibiotics; the Beta-lactams. AmpC is found in many bacteria including P. aeruginosa, a pathogen that causes life-threatening infections in cystic fibrosis patients. AmpC production depends on two highly conserved proteins: AmpR and NagZ. When beta-lactams are present, these enzymes turn on AmpC production to destroy the antibiotic and promote bacterial survival. AmpC is resistant to many clinically available antibiotics, so we are developing new molecules that block AmpR and NagZ function in order to make bacteria containing AmpC susceptible to beta-lactams.In collaboration with colleagues, a number of potent and highly selective NagZ inhibitors have been developed and we have crystallized them in complex with NagZ from Vibrio cholerae. We have also crystallized the enzyme in complex with two substrate analogues. The crystal structure of the apo form of NagZ has already been determined to 1.8 A resolution. We propose to collect high-resolution X-ray diffraction data sets from these NagZ complexes to determine the structural basis for the potency and selectivity of our inhibitors and to better understand the catalytic mechanism of NagZ and how it recognizes its natural substrate. Our in-house studies indicate these crystals should diffract to better than 1.5 A using synchrotron radiation. Finally, we have recently crystallized the regulatory domain of Citrobacter freundii AmpR. The crystals diffract to ~2.0 A in-house. High-resolution data collection from these crystals will be used in the determination of the AmpR crystal structure in complex with analogues of the product produced by NagZ will provide insight into its regulation and future drug design efforts.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Biotechnology Resource Grants (P41)
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University of Chicago
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