Skip to Main Content
Frequently Asked Questions
Submit an ETD
Global Search Box
Need Help?
Keyword Search
Participating Institutions
Advanced Search
School Logo
Files
File List
Bergstrom Dissertation Final 5 20180419.pdf (2.85 MB)
ETD Abstract Container
Abstract Header
SPECTROSCOPIC AND MECHANISTIC STUDIES OF METALLO-BETA-LACTAMASE INHIBITORS AND THE STRUCTURE-FUNCTION RELATIONSHIP OF NEW DELHI METALLO-BETA-LACTAMASE VARIANTS
Author Info
Bergstrom, Alexander R
ORCID® Identifier
http://orcid.org/0000-0003-2774-2189
Permalink:
http://rave.ohiolink.edu/etdc/view?acc_num=miami1524154064246174
Abstract Details
Year and Degree
2018, Doctor of Philosophy, Miami University, Chemistry and Biochemistry.
Abstract
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.
Committee
Michael Crowder (Advisor)
David Tierney (Committee Chair)
Pages
153 p.
Subject Headings
Biochemistry
;
Inorganic Chemistry
Keywords
antibiotic resistance
;
metallo-b-lactamase
;
metallo-beta-lactamase
;
lactamase
;
MBL
;
NDM
;
IMP
;
VIM
;
NMR
;
EPR
;
UV-vis
;
spectroscopy
;
inhibitors
;
drug discovery
Recommended Citations
Refworks
EndNote
RIS
Mendeley
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)
Abstract Footer
Document number:
miami1524154064246174
Download Count:
514
Copyright Info
© 2018, some rights reserved.
SPECTROSCOPIC AND MECHANISTIC STUDIES OF METALLO-BETA-LACTAMASE INHIBITORS AND THE STRUCTURE-FUNCTION RELATIONSHIP OF NEW DELHI METALLO-BETA-LACTAMASE VARIANTS by Alexander R Bergstrom is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by Miami University and OhioLINK.