Development of lanthipeptide engineering strategies

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.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemistry

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2019

Author dc:creator

• Hetrick, Kenton John

Contributors dc:contributor

• van der Donk, Wilfred A.
• Hergenrother, Paul J.
• Silverman, Scott K.
• Chan, Jefferson

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

Statement dc:rights

• Copyright 2018 Kenton John Hetrick

Language dc:language

en

Handle dc:identifier

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

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/102891