INHIBITOR RESISTANCE MECHANISMS AND INHIBITOR DESIGN IN ¿¿-LACTAMASES

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.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Biochemistry

Grantor dc:publisher

Case Western Reserve University School of Graduate Studies

Year dc:date

2013

Author dc:creator

• Rodkey, Elizabeth A.

Contributors dc:contributor

• van den Akker, Focco
• Shoham, Menachem

• Biochemistry
• SHV-1
• beta-lactamase
• inhibitor-resistant
• inhibition mechanism
• inhibitor design

Statement dc:rights

• unrestricted
• This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.

Language dc:language

English

Repository record dc:identifier

http://rave.ohiolink.edu/etdc/view?acc_num=case1354463033

OAI identifier oai:identifier

oai:etd.ohiolink.edu:case1354463033