{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/121186"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/121186","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"Development of LolCDE inhibitors as microbiome-sparing gram-negative-selective antibiotics","abstract":"Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2025-08-01","abstract_html":"Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2025-08-01","abstract_has_math":false,"creators":["Munoz, Kristen Adriane"],"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","Van Der Donk, Wilfred A","Metcalf, William W","Chan, Jefferson K"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2023,"date_issued":"2023-08","date_published":"2023-08","updated_at":"2026-07-22T22:24:57Z","subjects":["Gram-negative Bacteria","Gram-negative Antibiotics","Gut Microbiome","Narrow-spectrum","Microbiome-sparing"],"languages":["en","eng"],"rights":["Copyright 2023 Kristen Munoz"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/2142/121186","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Hergenrother, Paul J","Van Der Donk, Wilfred A","Metcalf, William W","Chan, Jefferson K"]},{"key":"dc:creator","label":"Author","values":["Munoz, Kristen Adriane"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2023-08","2023-05-10"]},{"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":["Gram-negative Bacteria","Gram-negative Antibiotics","Gut Microbiome","Narrow-spectrum","Microbiome-sparing"]}]},{"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 2023 Kristen Munoz"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/2142/121186"]}]},{"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 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","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."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Development of LolCDE inhibitors as microbiome-sparing gram-negative-selective antibiotics"]}]}],"canonical_facts":{"dc:contributor":["Hergenrother, Paul J","Van Der Donk, Wilfred A","Metcalf, William W","Chan, Jefferson K"],"dc:creator":["Munoz, Kristen Adriane"],"dc:date":["2023-08","2023-05-10"],"dc:description":["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","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."],"dc:format":["application/pdf"],"dc:identifier":["https://hdl.handle.net/2142/121186"],"dc:language":["en","eng"],"dc:rights":["Copyright 2023 Kristen Munoz"],"dc:subject":["Gram-negative Bacteria","Gram-negative Antibiotics","Gut Microbiome","Narrow-spectrum","Microbiome-sparing"],"dc:title":["Development of LolCDE inhibitors as microbiome-sparing gram-negative-selective 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":"2026-07-22T22:24:57Z"}