Targeting Bacterial Tolerance and Resistance with Small Molecules Open Access

Abstract

The overuse and misuse of antibiotics has put evolutionary pressure on bacteria to alter or bypass the targets of drugs or otherwise develop resistance, rendering a large percentage of our available medicines and pesticides ineffective. Novel antibiotics are quickly met with resistance, and treatment efforts are further complicated by bacterial tolerance mechanisms. Altogether we are facing a perfect storm of resistance and tolerance which threatens to kill millions and unravel our current approach to medicine in the process. I have focused my research efforts on two classes of molecules: 1) synthetic retinoids that can kill bacterial persisters with low resistance development potential, and 2) small molecule inhibitors of LexA, the gatekeeper of the bacterial SOS response.

Table of Contents

Chapter 1. Introduction. 1

1.1 A Brief History. 1

1.2 Antibiotic Overview.. 4

1.3 Resistance. 8

1.4 Tolerance and Persistence. 15

1.5 Current Outlook. 20

Chapter 2. Anti-MRSA Retinoids. 23

2.1 Methicillin-resistant Staphylococcus aureus. 23

2.2 Staphylococcus aureus Persistence. 25

2.3 Retinoids and CD437. 26

2.4 Anti-MRSA Retinoids. 28

2.5 Role of Globularity in Anti-MRSA Activity. 30

Chapter 3. Expanding the Retinoid Spectrum.. 37

3.1 Targeting Gram-negative Bacteria. 37

3.2 Applying eNTRy Rules to Membrane Perturbing Antibiotics. 40

Chapter 4. Small Molecule Inhibitors of LexA.. 44

4.1 Stress Responses. 44

4.1.1 Biofilms. 45

4.1.2 Endospores. 46

4.1.3 Filamentation. 48

4.2 The SOS Response. 49

4.3 Small Molecule Inhibitors of LexA.. 50

4.4 Expanded SAR Library. 52

References. 55

Supporting Information. 71

Chapter 2 Supporting Information. 71

Chapter 3 Supporting Information. 136

Chapter 3 Supporting Information. 147

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	resistance antibacterials antibiotics bacteria medicinal chemistry tolerance synthesis
Committee Chair / Thesis Advisor	William Wuest, Emory University
Committee Members	Dennis Liotta, Emory University Simon Blakey, Emory University

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