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INHIBITOR RESISTANCE MECHANISMS AND INHIBITOR DESIGN IN ¿¿-LACTAMASES

Rodkey, Elizabeth A.
http://rave.ohiolink.edu/etdc/view?acc_num=case1354463033

Abstract Details

2013, Doctor of Philosophy, Case Western Reserve University, Biochemistry.
Antibiotic resistance is an ever-present problem and is a natural result of evolution; however, it is anticipated that we may exhaust our antibacterial options if new antibiotics are not developed at the speed required by bacterial evolution. ¿¿-Lactams are commonly prescribed antibiotics and ¿¿-lactamases are major contributors to antibiotic resistance. While the fields of ¿¿-lactams, ¿¿-lactamases and ¿¿-lactamase inhibition are well studied and understood; there exist several knowledge gaps that can further our understanding of these mechanisms. By filling these gaps, we can gain a more detailed understanding of ¿¿-lactamase inhibition and facilitate the design of new and highly effective ¿¿-lactamase inhibitors. This in turn will prolong the efficacy of existing ¿¿-lactams. Likewise, because ¿¿-lactamase inhibitors have high structural similarity to ¿¿-lactams, information gleaned from the study of the former will inform on the design of the latter. Using X-ray crystallography, kinetic and antimicrobial susceptibility data, we describe several ¿¿-lactamase inhibitors (close and distant derivatives of those clinically available) and several ¿¿-lactamase enzyme mutants. The structural studies allow us to understand initial inhibitor binding, visualize enzyme active-site topology and inhibitor moiety binding modes and detail the mechanisms of inhibitor resistance. Additionally, the kinetic and antimicrobial susceptibility data allow us to gauge the efficacy of our experimental ¿¿-lactamase inhibitors. Together these data take us closer to developing ¿¿-lactamase inhibitors that have high affinity for the active site and are active against wild-type and/or inhibitor-resistant enzymes. Such inhibitors would help to ensure that antibiotic therapy continues to be effective.
Focco van den Akker (Advisor)
Menachem Shoham (Committee Chair)
Robert Bonomo (Committee Member)
Paul Carey (Committee Member)
Marion Skalweit (Committee Member)
144 p.
Biochemistry
SHV-1; beta-lactamase; inhibitor-resistant; inhibition mechanism; inhibitor design

Recommended Citations

Citations

  • Rodkey, E. A. (2013). INHIBITOR RESISTANCE MECHANISMS AND INHIBITOR DESIGN IN ¿¿-LACTAMASES [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1354463033

    APA Style (7th edition)

  • Rodkey, Elizabeth. INHIBITOR RESISTANCE MECHANISMS AND INHIBITOR DESIGN IN ¿¿-LACTAMASES. 2013. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1354463033.

    MLA Style (8th edition)

  • Rodkey, Elizabeth. "INHIBITOR RESISTANCE MECHANISMS AND INHIBITOR DESIGN IN ¿¿-LACTAMASES." Doctoral dissertation, Case Western Reserve University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=case1354463033

    Chicago Manual of Style (17th edition)

case1354463033
542
© 2012, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.