Date of Award

Spring 1-1-2016

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry & Biochemistry

First Advisor

Xiang Wang

Second Advisor

Tad H. Koch

Third Advisor

Richard Shoemaker

Fourth Advisor

Corrie Detweiler

Fifth Advisor

Maciej Walczak

Abstract

Antibiotics are essential to modern medicine. They have enabled surgery to become routine and allowed for the development of advanced treatments for cancer and burn patients. However, a reservoir of genes that confer resistance and aid in host colonization is distributed across the microbial world and decreases the ability of modern medicine to control infection. We have not been able to sustainably counteract this with new drugs and resistance has been observed for all antibiotics that have been employed in the clinic. New classes of antibiotics are needed, but we also need to explore ways to restore the efficacy of antibiotics made obsolete because of resistance.

A variety of small-molecules can be used to reverse antibiotic resistance; these compounds have been named resistance modifying agents or RMAs. In this dissertation, a summary of antibiotic resistance will be presented alongside antibiotic drug discovery strategies. These topics will highlight the importance of my research to address antibiotic resistance in S. aureus with tricyclic indoline alkaloids.

In Chapter 2, I will report the discovery of N-benzyl tricyclic indolines as antibiotics with activity in methicillin sensitive S. aureus (MSSA) and multiple methicillin resistant S. aureus (MRSA) strains. Then I will discuss the structure-activity relationship (SAR) study that led to a more potent analogue of this antibiotic class.

In Chapter 3, I will discuss the property-guided synthesis of a novel tricyclic indoline RMA that is capable of re-sensitizing MRSA to methicillin and other β-lactam antibiotics. These RMAs have a unique aza-tricyclic indoline (ATI) core structure that was inspired by natural products and cLogD7.4 calculations. To synthesize ATIs, we developed a new synthetic route that incorporated a robust gold-catalyzed tandem cyclization. This new route has led to a potent RMA for β-lactam antibiotics with the ATI core. This RMA has excellent physical properties and is now a candidate for preclinical studies.

Share

COinS