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van der Donk, Wilfred A. van der Donk, Wilfred A. Hergenrother, Paul J. Silverman, Scott K. Chan, Jefferson Hetrick, Kenton John 2019-02-08T18:39:39Z 2019-02-08T18:39:39Z 2021-02-09T10:15:26Z 2018-09-07 2018-12 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). No. of bitstreams: 3 HETRICK-DISSERTATION-2018.pdf: 4718731 bytes, checksum: 45e7b6ffbbeef38f3778432c53097d3a (MD5) LICENSE.txt: 4211 bytes, checksum: 8d2f6e83268122a086f68b7636468579 (MD5) PROQUEST_LICENSE.txt: 4557 bytes, checksum: 7030c0200330e99187b24e52e7ae06bb (MD5) Previous issue date: 2018-09-07 Embargo set by: Seth Robbins for item 109917 Lift date: 2021-02-08T18:40:00Z Reason: Author requested closed access (OA after 2yrs) in Vireo ETD system Embargo set by: Seth Robbins for item 109917 Lift date: 2021-02-08T18:42:23Z Reason: Author requested closed access (OA after 2yrs) in Vireo ETD system Embargo set by: Seth Robbins for item 109917 Lift date: 2021-02-08T18:43:54Z Reason: Author requested closed access (OA after 2yrs) in Vireo ETD system Embargo set by: Seth Robbins for item 109917 Lift date: 2021-02-08T18:44:50Z Reason: Author requested closed access (OA after 2yrs) in Vireo ETD system Limited Restriction Lifted for Item 109917 on 2021-02-09T10:15:26Z. application/pdf http://hdl.handle.net/2142/102891 en Copyright 2018 Kenton John Hetrick lanthipeptides ribosomally synthesized and post-translationally modified peptides phage display lanthipeptide engineering Development of lanthipeptide engineering strategies text text Chemistry Chemistry University of Illinois at Urbana-Champaign Dissertation Ph.D.