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Hergenrother, Paul J. Hergenrother, Paul J. Mitchell, Douglas A. van der Donk, Wilfred A. Zimmerman, Steve C. Garcia, Alfredo 2019-08-23T20:44:31Z 2019-08-23T20:44:31Z 2021-08-24T09:15:16Z 2019-02-20 2019-05 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). 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. application/pdf http://hdl.handle.net/2142/105134 en Copyright 2019 Alfredo Garcia Ring distortion sinomenine fusidic acid prodrug broad-spectrum antibiotic Ring distortion of the alkaloid sinomenine and novel prodrug approaches to broad-spectrum antibiotics text text Chemistry Chemistry University of Illinois at Urbana-Champaign Dissertation Ph.D.