{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/102891"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/102891","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"Development of lanthipeptide engineering strategies","abstract":"Natural products have long been an important source of therapeutic compounds. The lanthipeptides, members of the ribosomally synthesized and post-translationally modified peptide class of natural products, have potential applications ranging from clinical imaging to cystic fibrosis treatment. Additionally, many lanthipeptides possess strong antimicrobial activity, making them particularly intriguing given the on-going antimicrobial resistance crisis. However, like most natural products, lanthipeptides generally require optimization to make them more suitable for therapeutic uses, and there is a pressing need to develop platforms and strategies that enable the exploitation of lanthipeptide activities for clinical applications. Three strategies were explored to achieve this goal. First, a yeast display platform was used to select a precursor to a lanthipeptide that binds its biosynthetic enzymes more tightly, potentially enabling further biochemical characterization of a key substrate-enzyme interaction required for lanthipeptide biosynthesis. Second, the antimicrobial lanthipeptide nisin was displayed on the surface of a M13 phage, and this display platform was used to select for a nisin variant that binds the small molecule target lipid II. Finally, the ability of the nisin-displaying phage to function as a broad host-range virion with potential applications in the genetic transformation of difficult-to-transform bacteria or in a therapeutic setting was demonstrated. Together, these studies further expand the possible platforms for engineering and utilizing lanthipeptides.","abstract_html":"Natural products have long been an important source of therapeutic compounds. The lanthipeptides, members of the ribosomally synthesized and post-translationally modified peptide class of natural products, have potential applications ranging from clinical imaging to cystic fibrosis treatment. Additionally, many lanthipeptides possess strong antimicrobial activity, making them particularly intriguing given the on-going antimicrobial resistance crisis. However, like most natural products, lanthipeptides generally require optimization to make them more suitable for therapeutic uses, and there is a pressing need to develop platforms and strategies that enable the exploitation of lanthipeptide activities for clinical applications. Three strategies were explored to achieve this goal. First, a yeast display platform was used to select a precursor to a lanthipeptide that binds its biosynthetic enzymes more tightly, potentially enabling further biochemical characterization of a key substrate-enzyme interaction required for lanthipeptide biosynthesis. Second, the antimicrobial lanthipeptide nisin was displayed on the surface of a M13 phage, and this display platform was used to select for a nisin variant that binds the small molecule target lipid II. Finally, the ability of the nisin-displaying phage to function as a broad host-range virion with potential applications in the genetic transformation of difficult-to-transform bacteria or in a therapeutic setting was demonstrated. Together, these studies further expand the possible platforms for engineering and utilizing lanthipeptides.","abstract_has_math":false,"creators":["Hetrick, Kenton John"],"institution":"University of Illinois at Urbana-Champaign","degree_name":"Ph.D.","degree_level":"Dissertation","degree_discipline":"Chemistry","degree_department":null,"school":null,"contributors":["van der Donk, Wilfred A.","Hergenrother, Paul J.","Silverman, Scott K.","Chan, Jefferson"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2019,"date_issued":"2019-02-08T18:39:39Z","date_published":"2019-02-08T18:39:39Z","updated_at":"2026-07-22T22:24:42Z","subjects":["lanthipeptides","ribosomally synthesized and post-translationally modified peptides","phage display","lanthipeptide engineering"],"languages":["en"],"rights":["Copyright 2018 Kenton John Hetrick"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/2142/102891","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["van der Donk, Wilfred A.","Hergenrother, Paul J.","Silverman, Scott K.","Chan, Jefferson"]},{"key":"dc:creator","label":"Author","values":["Hetrick, Kenton John"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2019-02-08T18:39:39Z","2021-02-09T10:15:26Z","2018-09-07","2018-12"]},{"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":["lanthipeptides","ribosomally synthesized and post-translationally modified peptides","phage display","lanthipeptide engineering"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]},{"key":"dc:rights","label":"Dc Rights","values":["Copyright 2018 Kenton John Hetrick"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/2142/102891"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Natural products have long been an important source of therapeutic compounds. The lanthipeptides, members of the ribosomally synthesized and post-translationally modified peptide class of natural products, have potential applications ranging from clinical imaging to cystic fibrosis treatment. Additionally, many lanthipeptides possess strong antimicrobial activity, making them particularly intriguing given the on-going antimicrobial resistance crisis. However, like most natural products, lanthipeptides generally require optimization to make them more suitable for therapeutic uses, and there is a pressing need to develop platforms and strategies that enable the exploitation of lanthipeptide activities for clinical applications. Three strategies were explored to achieve this goal. First, a yeast display platform was used to select a precursor to a lanthipeptide that binds its biosynthetic enzymes more tightly, potentially enabling further biochemical characterization of a key substrate-enzyme interaction required for lanthipeptide biosynthesis. Second, the antimicrobial lanthipeptide nisin was displayed on the surface of a M13 phage, and this display platform was used to select for a nisin variant that binds the small molecule target lipid II. Finally, the ability of the nisin-displaying phage to function as a broad host-range virion with potential applications in the genetic transformation of difficult-to-transform bacteria or in a therapeutic setting was demonstrated. Together, these studies further expand the possible platforms for engineering and utilizing lanthipeptides.","Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2020-12-01","The student, Kenton Hetrick, accepted the attached license on 2018-09-06 at 12:11.","The student, Kenton Hetrick, submitted this Dissertation for approval on 2018-09-06 at 12:18.","This Dissertation was approved for publication on 2018-09-07 at 09:48.","DSpace SAF Submission Ingestion Package generated from Vireo submission #12999 on 2019-02-08 at 11:37:51","Made available in DSpace on 2019-02-08T18:39:39Z (GMT). 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The lanthipeptides, members of the ribosomally synthesized and post-translationally modified peptide class of natural products, have potential applications ranging from clinical imaging to cystic fibrosis treatment. Additionally, many lanthipeptides possess strong antimicrobial activity, making them particularly intriguing given the on-going antimicrobial resistance crisis. However, like most natural products, lanthipeptides generally require optimization to make them more suitable for therapeutic uses, and there is a pressing need to develop platforms and strategies that enable the exploitation of lanthipeptide activities for clinical applications. Three strategies were explored to achieve this goal. First, a yeast display platform was used to select a precursor to a lanthipeptide that binds its biosynthetic enzymes more tightly, potentially enabling further biochemical characterization of a key substrate-enzyme interaction required for lanthipeptide biosynthesis. Second, the antimicrobial lanthipeptide nisin was displayed on the surface of a M13 phage, and this display platform was used to select for a nisin variant that binds the small molecule target lipid II. Finally, the ability of the nisin-displaying phage to function as a broad host-range virion with potential applications in the genetic transformation of difficult-to-transform bacteria or in a therapeutic setting was demonstrated. Together, these studies further expand the possible platforms for engineering and utilizing lanthipeptides.","Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2020-12-01","The student, Kenton Hetrick, accepted the attached license on 2018-09-06 at 12:11.","The student, Kenton Hetrick, submitted this Dissertation for approval on 2018-09-06 at 12:18.","This Dissertation was approved for publication on 2018-09-07 at 09:48.","DSpace SAF Submission Ingestion Package generated from Vireo submission #12999 on 2019-02-08 at 11:37:51","Made available in DSpace on 2019-02-08T18:39:39Z (GMT). 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