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Title:Stimulating antibiotic development by targeting virulence and facilitating natural product discovery
Author(s):Maxson, Tucker
Director of Research:Mitchell, Douglas A
Doctoral Committee Chair(s):Mitchell, Douglas A
Doctoral Committee Member(s):Hergenrother, Paul J; Burke, Martin D; Blanke, Steven R
Department / Program:Chemistry
Discipline:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):virulence
nelfinavir
CaaX protease
natural products
reactivity based screening
Abstract:Antibiotics are a cornerstone of modern medicine and have drastically reduced the burden of infectious diseases. Unfortunately, resistance to all clinically used antibiotics has become a major challenge that is exacerbated by numerous difficulties surrounding the development of new drugs. However, inventive strategies to overcome resistance as well as discover novel antibiotics are increasingly being explored. Whereas traditional antibiotics were generally designed to directly kill as many species of bacteria as possible, several new approaches have focused on narrower spectrum agents that have significant potential benefits. Antibiotics active against only one or a small group of pathogens would spare the microbiome, which may decrease the risk of secondary infections and slow the spread of resistance. One such narrow-spectrum strategy is to target the virulence factors employed by pathogens during an infection. In chapter 2, I demonstrate that the FDA approved HIV protease inhibitor nelfinavir can be repurposed as an inhibitor of the biosynthesis of the Streptococcus pyogenes cytolytic toxin streptolysin S. Nelfinavir was utilized to explore the proteolytic processing step in streptolysin S biosynthesis and was also shown to inhibit toxin production in other pathogens known to harbor similar biosynthetic clusters. Another approach to the problem of finding new antibiotics can be found in facilitating natural product discovery. Many antibiotics are derived from natural products but continuing to find new compounds has become increasingly difficult, especially due to rediscovery of known natural products. To help circumvent this problem, I developed a probe for identifying natural products containing aldehydes and ketones from microbial extracts based on the chemical reactivity of those carbonyl functional groups (chapter 3). This method is agnostic to the activity of the product and allows for the rapid identification of low abundance compounds that may be missed through activity-based screening. I demonstrate the utility of this probe by screening a collection of bacterial extracts, leading to the discovery of an analog of the protease inhibitor antipain.
Issue Date:2016-04-19
Type:Thesis
URI:http://hdl.handle.net/2142/90486
Rights Information:Copyright 2016 Tucker Maxson
Date Available in IDEALS:2016-07-07
Date Deposited:2016-05


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