Development of lanthipeptide engineering strategies

Hetrick, Kenton John

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https://hdl.handle.net/2142/102891 Copy

Description

Title

Development of lanthipeptide engineering strategies

Author(s)

Hetrick, Kenton John

Issue Date

2018-09-07

Director of Research (if dissertation) or Advisor (if thesis)

van der Donk, Wilfred A.

Doctoral Committee Chair(s)

van der Donk, Wilfred A.

Committee Member(s)

• Hergenrother, Paul J.
• Silverman, Scott K.
• Chan, Jefferson

Department of Study

Chemistry

Discipline

Chemistry

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• lanthipeptides
• ribosomally synthesized and post-translationally modified peptides
• phage display
• lanthipeptide engineering

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.

Graduation Semester

2018-12

Type of Resource

text

Permalink

http://hdl.handle.net/2142/102891

Copyright and License Information

Copyright 2018 Kenton John Hetrick

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