Chemical Tools to Combat Antibiotic Resistance: Design, Synthesis, and Biological Evaluation of Antibiotic Natural Products and Adjuvants Restricted; Files & ToC

Abstract

Antibiotic therapy is a critical pillar of modern medicine, but its continued clinical use is threatened by the rapid spread of antimicrobial resistance. This work presents two complementary strategies to combat antimicrobial resistance: 1) The development of novel antibiotic adjuvants; and 2) The discovery of novel antibiotic mechanisms of action. Adjuvants which potentiate the activity of β-lactams against β-lactamase-producing resistant bacteria have seen widespread clinical use, but the same strategy has not been successfully applied to other antibiotic classes. Aminoglycoside antibiotics are highly sensitive to resistance mediated by 16S ribosomal RNA methyltransferase enzymes, presenting an opportunity to develop novel “resistance breakers.” This work describes the discovery of small molecule inhibitors of this enzyme class. We developed a novel synthetic route to access several series of rationally designed dehydroamino amide compounds and evaluated their biochemical potency against 16S ribosomal methyltransferases NpmA and RmtB, representing the first reported efforts against these targets. In a separate approach, we sought to use the antibacterial natural product pestalachloride B as a tool compound to discover novel antibiotic mechanisms. This work describes efforts toward the first total synthesis of pestalachloride B and the design of photoaffinity probes designed around its inherent benzophenone moiety. The exploration of these two strategies has led to several discoveries related to organic synthesis and provides a platform for further investigation in the future. 

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About this Dissertation

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School	Laney Graduate School
Department	Chemistry
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Chemistry, Organic
Keyword	English bacteria pestalone medicinal natural pestalachloride RmtB organic products chemistry antibiotic methyltransferase NpmA
Committee Chair / Thesis Advisor	William M. Wuest, Emory University
Committee Members	Dennis C. Liotta, Emory University Simon B. Blakey, Emory University

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