{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/125786"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/125786","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"Physicochemical trends of compound efflux in gram-negative bacteria and characterization of novel antibacterials","abstract":"Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2026-08-01","abstract_html":"Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2026-08-01","abstract_has_math":false,"creators":["Ulrich, Rebecca Joy"],"institution":"University of Illinois at Urbana-Champaign","degree_name":"Ph.D.","degree_level":"Dissertation","degree_discipline":"Chemistry","degree_department":null,"school":null,"contributors":["Hergenrother, Paul J.","Hergenrother, Paul J","Burke, Martin D","Metcalf, William W","Manesis, Anastasia C"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2024,"date_issued":"2024-08","date_published":"2024-08","updated_at":"2026-07-22T22:25:02Z","subjects":["Compound Efflux","Accumulation","Lolcde","Fabi","Gram Negative Bacteria"],"languages":["en","eng"],"rights":["Copyright Rebecca J. Ulrich 2024"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/2142/125786","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Hergenrother, Paul J.","Hergenrother, Paul J","Burke, Martin D","Metcalf, William W","Manesis, Anastasia C"]},{"key":"dc:creator","label":"Author","values":["Ulrich, Rebecca Joy"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2024-08","2024-07-09"]},{"key":"dc:type","label":"Dc Type","values":["text","Thesis"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Chemistry"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Ph.D."]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of Illinois at Urbana-Champaign"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Compound Efflux","Accumulation","Lolcde","Fabi","Gram Negative Bacteria"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en","eng"]},{"key":"dc:rights","label":"Dc Rights","values":["Copyright Rebecca J. Ulrich 2024"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/2142/125786"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2026-08-01","The student, Rebecca Ulrich, accepted the attached license on 2024-07-04 at 20:05.","The student, Rebecca Ulrich, submitted this Dissertation for approval on 2024-07-04 at 20:10.","This Dissertation was approved for publication on 2024-07-09 at 16:55.","DSpace SAF Submission Ingestion Package generated from Vireo submission #20950 on 2025-02-04 at 21:25:24","Multi-drug resistant bacterial infections are a rising threat to human health and account for 1.3 million deaths annually, and 70% of these deaths are due to gram negative pathogens. No new FDA-approved classes of gram-negative active antibiotics have entered the clinic in the past 55 years, due to challenges with converting in vitro biochemical activity to whole cell gram negative activity. Gram negative drug discovery is hindered by both an impermeable outer membrane, which limits compound uptake, and promiscuous efflux pumps, which rapidly expel antibiotics. While previous work in the Hergenrother lab has developed actionable guidelines for imbuing gram negative activity into antibacterials, compound efflux remains a significant issue limiting efficacy of small molecules. Herein, we report the development and validation of an LC-MS/MS assay to quantify efflux liabilities (EffluX Propensity EvaLuation, EXPEL) and application of the EXPEL assay to a complex and diverse collection of compounds to identify physicochemical properties that correlate with efflux. Through chemoinformatic data analysis, actionable guidelines for engineering efflux liabilities out of small molecules were identified. Using these guidelines, we are strategically modifying gram-negative active and microbiome sparing LolCDE and FabI inhibitors, both which have excellent preclinical properties, to evade efflux. Additionally, we present other candidate compounds for applying the EXPEL rules and provide a blueprint for optimizing compound uptake and efflux evasion in antibacterial candidates. Additionally, ongoing work in the Hergenrother lab focuses on the development of gram negative active antibacterials and continued expansion of our understanding of porin-mediated uptake in E. coli. Work towards the development of 3 antibacterials as gram negative antibiotics—lolamicin, fabimycin, and Ribocil-PA—is presented herein, as well as work towards understanding mechanisms of porin-mediated uptake and the role of stereochemistry on uptake and efflux in E. coli."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Physicochemical trends of compound efflux in gram-negative bacteria and characterization of novel antibacterials"]}]}],"canonical_facts":{"dc:contributor":["Hergenrother, Paul J.","Hergenrother, Paul J","Burke, Martin D","Metcalf, William W","Manesis, Anastasia C"],"dc:creator":["Ulrich, Rebecca Joy"],"dc:date":["2024-08","2024-07-09"],"dc:description":["Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2026-08-01","The student, Rebecca Ulrich, accepted the attached license on 2024-07-04 at 20:05.","The student, Rebecca Ulrich, submitted this Dissertation for approval on 2024-07-04 at 20:10.","This Dissertation was approved for publication on 2024-07-09 at 16:55.","DSpace SAF Submission Ingestion Package generated from Vireo submission #20950 on 2025-02-04 at 21:25:24","Multi-drug resistant bacterial infections are a rising threat to human health and account for 1.3 million deaths annually, and 70% of these deaths are due to gram negative pathogens. No new FDA-approved classes of gram-negative active antibiotics have entered the clinic in the past 55 years, due to challenges with converting in vitro biochemical activity to whole cell gram negative activity. Gram negative drug discovery is hindered by both an impermeable outer membrane, which limits compound uptake, and promiscuous efflux pumps, which rapidly expel antibiotics. While previous work in the Hergenrother lab has developed actionable guidelines for imbuing gram negative activity into antibacterials, compound efflux remains a significant issue limiting efficacy of small molecules. Herein, we report the development and validation of an LC-MS/MS assay to quantify efflux liabilities (EffluX Propensity EvaLuation, EXPEL) and application of the EXPEL assay to a complex and diverse collection of compounds to identify physicochemical properties that correlate with efflux. Through chemoinformatic data analysis, actionable guidelines for engineering efflux liabilities out of small molecules were identified. Using these guidelines, we are strategically modifying gram-negative active and microbiome sparing LolCDE and FabI inhibitors, both which have excellent preclinical properties, to evade efflux. Additionally, we present other candidate compounds for applying the EXPEL rules and provide a blueprint for optimizing compound uptake and efflux evasion in antibacterial candidates. Additionally, ongoing work in the Hergenrother lab focuses on the development of gram negative active antibacterials and continued expansion of our understanding of porin-mediated uptake in E. coli. Work towards the development of 3 antibacterials as gram negative antibiotics—lolamicin, fabimycin, and Ribocil-PA—is presented herein, as well as work towards understanding mechanisms of porin-mediated uptake and the role of stereochemistry on uptake and efflux in E. coli."],"dc:format":["application/pdf"],"dc:identifier":["https://hdl.handle.net/2142/125786"],"dc:language":["en","eng"],"dc:rights":["Copyright Rebecca J. Ulrich 2024"],"dc:subject":["Compound Efflux","Accumulation","Lolcde","Fabi","Gram Negative Bacteria"],"dc:title":["Physicochemical trends of compound efflux in gram-negative bacteria and characterization of novel antibacterials"],"dc:type":["text","Thesis"],"thesis:degree_discipline":["Chemistry"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Ph.D."],"thesis:institution_name":["University of Illinois at Urbana-Champaign"]},"updated_at":"2026-07-22T22:25:02Z"}