{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/105134"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/105134","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"Ring distortion of the alkaloid sinomenine and novel prodrug approaches to broad-spectrum antibiotics","abstract":"The continual rise of microbial resistance is a pressing concern throughout the world, resulting in several thousands of deaths each year. Most of these deaths are a result of Gram-negative infections as no new class of Gram-negative antibiotics has been introduced in several decades. The problematic nature of this epidemic lies in the composition of the Gram-negative bacterial membrane, as it is impermeable to most organic small-molecules. The eNTRy rules, developed by the Hergenrother lab, can guide the synthesis of Gram-negative-active antibiotic leads as they predict the likelihood of compound accumulation in Gram-negative bacteria. In general, for a compound to accumulate in Gram-negative bacteria, it must possess an ionizable nitrogen, be relatively flat, and rigid. A major hurdle to this approach is installation of the nitrogen without disturbing target engagement. A solution to this involves appendage of ionizable nitrogens on a prodrug moiety such that it crosses the outer membrane and is cleaved within Gram-negative bacteria, releasing the active antibiotic. Such novel strategy can be a powerful approach to combat disease-causing pathogens as it addresses the major limitation of discovering new broad-spectrum antibiotics: passage across the outer membrane, and ultimately accumulation. The chapters herein emphasize the importance of combating antibiotic resistance, specifically against Gram-negatives, and provide actionable strategies by which to accomplish this mission. Chapter 1 focuses on the challenges of generating Gram-negative actives and describes novel solutions to this problem. This chapter also describes the structure-activity relationship of Gram-positive only antibiotic fusidic acid. Chapter 2 discusses the ring distortion of the alkaloid sinomenine using the complexity-to-diversity (CtD) approach to generate 66 total compounds, which played a key role in identifying the 3-dimensionality parameter, globularity (Glob), as important for accumulation in Gram-negative bacteria, and eventual discovery of the eNTRy rules. Chapter 3 describes our initial efforts to convert fusidic acid using the eNTRy rules and then describes the success of this conversion target using a novel polyamine amidoxime ester prodrug strategy.","abstract_html":"The continual rise of microbial resistance is a pressing concern throughout the world, resulting in several thousands of deaths each year. Most of these deaths are a result of Gram-negative infections as no new class of Gram-negative antibiotics has been introduced in several decades. The problematic nature of this epidemic lies in the composition of the Gram-negative bacterial membrane, as it is impermeable to most organic small-molecules. The eNTRy rules, developed by the Hergenrother lab, can guide the synthesis of Gram-negative-active antibiotic leads as they predict the likelihood of compound accumulation in Gram-negative bacteria. In general, for a compound to accumulate in Gram-negative bacteria, it must possess an ionizable nitrogen, be relatively flat, and rigid. A major hurdle to this approach is installation of the nitrogen without disturbing target engagement. A solution to this involves appendage of ionizable nitrogens on a prodrug moiety such that it crosses the outer membrane and is cleaved within Gram-negative bacteria, releasing the active antibiotic. Such novel strategy can be a powerful approach to combat disease-causing pathogens as it addresses the major limitation of discovering new broad-spectrum antibiotics: passage across the outer membrane, and ultimately accumulation. The chapters herein emphasize the importance of combating antibiotic resistance, specifically against Gram-negatives, and provide actionable strategies by which to accomplish this mission. Chapter 1 focuses on the challenges of generating Gram-negative actives and describes novel solutions to this problem. This chapter also describes the structure-activity relationship of Gram-positive only antibiotic fusidic acid. Chapter 2 discusses the ring distortion of the alkaloid sinomenine using the complexity-to-diversity (CtD) approach to generate 66 total compounds, which played a key role in identifying the 3-dimensionality parameter, globularity (Glob), as important for accumulation in Gram-negative bacteria, and eventual discovery of the eNTRy rules. Chapter 3 describes our initial efforts to convert fusidic acid using the eNTRy rules and then describes the success of this conversion target using a novel polyamine amidoxime ester prodrug strategy.","abstract_has_math":false,"creators":["Garcia, Alfredo"],"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.","Mitchell, Douglas A.","van der Donk, Wilfred A.","Zimmerman, Steve C."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2019,"date_issued":"2019-08-23T20:44:31Z","date_published":"2019-08-23T20:44:31Z","updated_at":"2026-07-22T22:24:44Z","subjects":["Ring distortion","sinomenine","fusidic acid","prodrug","broad-spectrum antibiotic"],"languages":["en"],"rights":["Copyright 2019 Alfredo Garcia"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/2142/105134","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Hergenrother, Paul J.","Mitchell, Douglas A.","van der Donk, Wilfred A.","Zimmerman, Steve C."]},{"key":"dc:creator","label":"Author","values":["Garcia, Alfredo"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2019-08-23T20:44:31Z","2021-08-24T09:15:16Z","2019-02-20","2019-05"]},{"key":"dc:type","label":"Dc Type","values":["text"]},{"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":["Ring distortion","sinomenine","fusidic acid","prodrug","broad-spectrum antibiotic"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]},{"key":"dc:rights","label":"Dc Rights","values":["Copyright 2019 Alfredo Garcia"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/2142/105134"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["The continual rise of microbial resistance is a pressing concern throughout the world, resulting in several thousands of deaths each year. Most of these deaths are a result of Gram-negative infections as no new class of Gram-negative antibiotics has been introduced in several decades. The problematic nature of this epidemic lies in the composition of the Gram-negative bacterial membrane, as it is impermeable to most organic small-molecules. The eNTRy rules, developed by the Hergenrother lab, can guide the synthesis of Gram-negative-active antibiotic leads as they predict the likelihood of compound accumulation in Gram-negative bacteria. In general, for a compound to accumulate in Gram-negative bacteria, it must possess an ionizable nitrogen, be relatively flat, and rigid. A major hurdle to this approach is installation of the nitrogen without disturbing target engagement. A solution to this involves appendage of ionizable nitrogens on a prodrug moiety such that it crosses the outer membrane and is cleaved within Gram-negative bacteria, releasing the active antibiotic. Such novel strategy can be a powerful approach to combat disease-causing pathogens as it addresses the major limitation of discovering new broad-spectrum antibiotics: passage across the outer membrane, and ultimately accumulation. The chapters herein emphasize the importance of combating antibiotic resistance, specifically against Gram-negatives, and provide actionable strategies by which to accomplish this mission. Chapter 1 focuses on the challenges of generating Gram-negative actives and describes novel solutions to this problem. This chapter also describes the structure-activity relationship of Gram-positive only antibiotic fusidic acid. Chapter 2 discusses the ring distortion of the alkaloid sinomenine using the complexity-to-diversity (CtD) approach to generate 66 total compounds, which played a key role in identifying the 3-dimensionality parameter, globularity (Glob), as important for accumulation in Gram-negative bacteria, and eventual discovery of the eNTRy rules. Chapter 3 describes our initial efforts to convert fusidic acid using the eNTRy rules and then describes the success of this conversion target using a novel polyamine amidoxime ester prodrug strategy.","Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2021-05-01","The student, Alfredo Garcia, accepted the attached license on 2019-02-18 at 12:18.","The student, Alfredo Garcia, submitted this Dissertation for approval on 2019-02-18 at 13:25.","This Dissertation was approved for publication on 2019-02-20 at 10:04.","DSpace SAF Submission Ingestion Package generated from Vireo submission #13392 on 2019-08-22 at 16:19:50","Made available in DSpace on 2019-08-23T20:44:31Z (GMT). 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Most of these deaths are a result of Gram-negative infections as no new class of Gram-negative antibiotics has been introduced in several decades. The problematic nature of this epidemic lies in the composition of the Gram-negative bacterial membrane, as it is impermeable to most organic small-molecules. The eNTRy rules, developed by the Hergenrother lab, can guide the synthesis of Gram-negative-active antibiotic leads as they predict the likelihood of compound accumulation in Gram-negative bacteria. In general, for a compound to accumulate in Gram-negative bacteria, it must possess an ionizable nitrogen, be relatively flat, and rigid. A major hurdle to this approach is installation of the nitrogen without disturbing target engagement. A solution to this involves appendage of ionizable nitrogens on a prodrug moiety such that it crosses the outer membrane and is cleaved within Gram-negative bacteria, releasing the active antibiotic. Such novel strategy can be a powerful approach to combat disease-causing pathogens as it addresses the major limitation of discovering new broad-spectrum antibiotics: passage across the outer membrane, and ultimately accumulation. The chapters herein emphasize the importance of combating antibiotic resistance, specifically against Gram-negatives, and provide actionable strategies by which to accomplish this mission. Chapter 1 focuses on the challenges of generating Gram-negative actives and describes novel solutions to this problem. This chapter also describes the structure-activity relationship of Gram-positive only antibiotic fusidic acid. Chapter 2 discusses the ring distortion of the alkaloid sinomenine using the complexity-to-diversity (CtD) approach to generate 66 total compounds, which played a key role in identifying the 3-dimensionality parameter, globularity (Glob), as important for accumulation in Gram-negative bacteria, and eventual discovery of the eNTRy rules. Chapter 3 describes our initial efforts to convert fusidic acid using the eNTRy rules and then describes the success of this conversion target using a novel polyamine amidoxime ester prodrug strategy.","Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2021-05-01","The student, Alfredo Garcia, accepted the attached license on 2019-02-18 at 12:18.","The student, Alfredo Garcia, submitted this Dissertation for approval on 2019-02-18 at 13:25.","This Dissertation was approved for publication on 2019-02-20 at 10:04.","DSpace SAF Submission Ingestion Package generated from Vireo submission #13392 on 2019-08-22 at 16:19:50","Made available in DSpace on 2019-08-23T20:44:31Z (GMT). No. of bitstreams: 4 GARCIA-DISSERTATION-2019.pdf: 19739036 bytes, checksum: b4a2572b30eef71e7a60deeb9b464e23 (MD5) Alfredo Garcia Dissertation.docx: 31151227 bytes, checksum: 0dfcd439201cc5c156ec5507d08fa983 (MD5) LICENSE.txt: 4211 bytes, checksum: 44918534f68ba590859ee0cbf0d72bfb (MD5) PROQUEST_LICENSE.txt: 4557 bytes, checksum: 0eb9566d18d6f1df875231021c008c35 (MD5) Previous issue date: 2019-02-20","Embargo set by: Seth Robbins for item 112253 Lift date: 2021-08-23T20:44:50Z Reason: Author requested closed access (OA after 2yrs) in Vireo ETD system","Embargo set by: Seth Robbins for item 112253 Lift date: 2021-08-23T20:46:41Z Reason: Author requested closed access (OA after 2yrs) in Vireo ETD system","Embargo set by: Seth Robbins for item 112253 Lift date: 2021-08-23T20:47:38Z Reason: Author requested closed access (OA after 2yrs) in Vireo ETD system","Embargo set by: Seth Robbins for item 112253 Lift date: 2021-08-23T20:48:32Z Reason: Author requested closed access (OA after 2yrs) in Vireo ETD system","Limited Restriction Lifted for Item 112253 on 2021-08-24T09:15:16Z."],"dc:format":["application/pdf"],"dc:identifier":["http://hdl.handle.net/2142/105134"],"dc:language":["en"],"dc:rights":["Copyright 2019 Alfredo Garcia"],"dc:subject":["Ring distortion","sinomenine","fusidic acid","prodrug","broad-spectrum antibiotic"],"dc:title":["Ring distortion of the alkaloid sinomenine and novel prodrug approaches to broad-spectrum antibiotics"],"dc:type":["text"],"thesis:degree_discipline":["Chemistry"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Ph.D."],"thesis:institution_name":["University of Illinois at Urbana-Champaign"]},"updated_at":"2026-07-22T22:24:44Z"}