2026-09-23T05:16:13Z https://www.ideals.illinois.edu/oai-pmh

oai:www.ideals.illinois.edu:2142/121186 2023-12-11 col_2142_5131 col_2142_14789 com_2142_5130 com_2142_14788 com_2142_8903

Hergenrother, Paul J Hergenrother, Paul J Van Der Donk, Wilfred A Metcalf, William W Chan, Jefferson K 2023-08 application/pdf en text Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2025-08-01 The student, Kristen Munoz, accepted the attached license on 2023-05-04 at 17:39. The student, Kristen Munoz, submitted this Dissertation for approval on 2023-05-04 at 17:48. This Dissertation was approved for publication on 2023-05-10 at 14:54. DSpace SAF Submission Ingestion Package generated from Vireo submission #19341 on 2023-12-04 at 17:29:48 https://hdl.handle.net/2142/121186 Copyright 2023 Kristen Munoz Development of LolCDE inhibitors as microbiome-sparing gram-negative-selective antibiotics Munoz, Kristen Adriane 2023-05-10 Gram-negative Bacteria Gram-negative Antibiotics Gut Microbiome Narrow-spectrum Microbiome-sparing Infections caused by gram-negative pathogens are on the rise and alarmingly, no new classes of antibiotics that target gram-negative bacteria have been approved by the Food and Drug Administration since the 1960s. Especially absent in our current antibiotic arsenal are gram-negative-only agents, with colistin being a notable exception that is exclusively used as a last resort for problematic gram-negative infections. Consequentially, gram-negative infections are typically treated with broad-spectrum antibiotics, resulting in damage to the gut microbiome and susceptibility to secondary diseases and infections. As such, there is a critical need for antibiotics that are selective for gram-negative bacteria over gram-positive bacteria, but also selective for pathogenic bacteria over commensal bacteria. Herein we report the development of a doubly selective strategy to design and discover lolamycin, a gram-negative-only antibiotic that targets the LolCDE lipoprotein transport system. Lolamycin has impressive activity against a panel of 125 multidrug-resistant clinical isolates, shows efficacy in multiple murine infection models whether dosed intraperitoneally or orally, spares the gut microbiome, and prevents secondary Clostridioides difficile infection. The selective killing of pathogenic gram-negative bacteria by lolamycin is a consequence of low sequence homology for the target in pathogenic bacteria versus commensals. With applications towards other bacterial proteins including BamA, LptD, or MsbA, this doubly selective strategy can serve as a blueprint for the development of microbiome-sparing antibiotics. Text eng Ph.D. Dissertation Chemistry University of Illinois at Urbana-Champaign Chemistry