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SPECTROSCOPIC AND MECHANISTIC STUDIES OF METALLO-BETA-LACTAMASE INHIBITORS AND THE STRUCTURE-FUNCTION RELATIONSHIP OF NEW DELHI METALLO-BETA-LACTAMASE VARIANTS

Abstract Details

2018, Doctor of Philosophy, Miami University, Chemistry and Biochemistry.
The rapid dissemination of antibiotic resistance genes has become a critical threat to human health. The most problematic mechanism by which bacteria confer resistance to antibiotics is via the expression of beta-lactamases, enzymes which hydrolyze one of the most important classes of antibiotics, beta-lactams. To extend the lifespan of current generation beta-lactams, significant effort has been dedicated to identifying beta-lactamase inhibitors. This strategy has proven successful with serine beta-lactamases; but to date, no clinical inhibitors of the metallo-beta-lactamases (MBLs) have been discovered. Of the MBLs, three are reported to pose the greatest threat worldwide: New Delhi MBL (NDM), Verona integron-encoded MBL (VIM), and imipenemase (IMP). The majority of this dissertation describes mechanistic studies on these three MBLs with several inhibitors that have been recently identified. Using kinetics, equilibrium dialysis, fluorimetry, UV-vis spectroscopy, 1H NMR spectroscopy, and electron paramagnetic resonance (EPR) spectroscopy, the interactions between the enzymes and inhibitors were illuminated. These data were then used to guide drug design and further optimize the inhibitors. Another focus of this dissertation was to explore differences between NDM variants. NDM, VIM, and IMP have each quickly evolved dozens of variants, and understanding how and why these mutations are occurring could provide valuable information for the development of clinical MBL inhibitors. Using a suite of spectroscopic techniques, structural and functional changes between NDM-1, -4, and -12 were identified.
Michael Crowder (Advisor)
David Tierney (Committee Chair)
153 p.

Recommended Citations

Citations

  • Bergstrom, A. R. (2018). SPECTROSCOPIC AND MECHANISTIC STUDIES OF METALLO-BETA-LACTAMASE INHIBITORS AND THE STRUCTURE-FUNCTION RELATIONSHIP OF NEW DELHI METALLO-BETA-LACTAMASE VARIANTS [Doctoral dissertation, Miami University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=miami1524154064246174

    APA Style (7th edition)

  • Bergstrom, Alexander. SPECTROSCOPIC AND MECHANISTIC STUDIES OF METALLO-BETA-LACTAMASE INHIBITORS AND THE STRUCTURE-FUNCTION RELATIONSHIP OF NEW DELHI METALLO-BETA-LACTAMASE VARIANTS. 2018. Miami University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=miami1524154064246174.

    MLA Style (8th edition)

  • Bergstrom, Alexander. "SPECTROSCOPIC AND MECHANISTIC STUDIES OF METALLO-BETA-LACTAMASE INHIBITORS AND THE STRUCTURE-FUNCTION RELATIONSHIP OF NEW DELHI METALLO-BETA-LACTAMASE VARIANTS." Doctoral dissertation, Miami University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=miami1524154064246174

    Chicago Manual of Style (17th edition)