{"id":{"repo_id":"ohiolink","oai_identifier":"oai:etd.ohiolink.edu:case1354463033"},"canonical_url":"https://search.dev.ndltd.org/etd/ohiolink/oai:etd.ohiolink.edu:case1354463033","repository":{"repo_id":"ohiolink","name":"OhioLINK","base_url":"https://etd.ohiolink.edu/acprod/odb_etd/ws/oai/oai"},"display":{"title":"INHIBITOR RESISTANCE MECHANISMS AND INHIBITOR DESIGN IN ¿¿-LACTAMASES","abstract":"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.","abstract_html":"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.","abstract_has_math":false,"creators":["Rodkey, Elizabeth A."],"institution":"Case Western Reserve University School of Graduate Studies","degree_name":"Doctor of Philosophy","degree_level":"doctoral","degree_discipline":"Biochemistry","degree_department":null,"school":null,"contributors":["van den Akker, Focco","Shoham, Menachem"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2013,"date_issued":"2013-03-08","date_published":"2013-03-08","updated_at":"2026-07-24T03:35:52Z","subjects":["Biochemistry","SHV-1","beta-lactamase","inhibitor-resistant","inhibition mechanism","inhibitor design"],"languages":["English"],"rights":["unrestricted","This thesis or dissertation is protected by copyright: all rights reserved. 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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."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf","p.144","3.82 MB"]},{"key":"dc:title","label":"Title","values":["INHIBITOR RESISTANCE MECHANISMS AND INHIBITOR DESIGN IN ¿¿-LACTAMASES"]}]}],"canonical_facts":{"dc:contributor":["van den Akker, Focco","Shoham, Menachem"],"dc:creator":["Rodkey, Elizabeth A."],"dc:date":["2013-03-08"],"dc:description":["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."],"dc:format":["application/pdf","p.144","3.82 MB"],"dc:identifier":["http://rave.ohiolink.edu/etdc/view?acc_num=case1354463033"],"dc:language":["English"],"dc:publisher":["Case Western Reserve University School of Graduate Studies / OhioLINK"],"dc:rights":["unrestricted","This thesis or dissertation is protected by copyright: all rights reserved. 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