Ring distortion of the alkaloid sinomenine and novel prodrug approaches to broad-spectrum antibiotics

The continual rise of microbial resistance is a pressing concern throughout the world, resulting in several thousands of deaths each year. Most of these deaths are a result of Gram-negative infections as no new class of Gram-negative antibiotics has been introduced in several decades. The problematic nature of this epidemic lies in the composition of the Gram-negative bacterial membrane, as it is impermeable to most organic small-molecules. The eNTRy rules, developed by the Hergenrother lab, can guide the synthesis of Gram-negative-active antibiotic leads as they predict the likelihood of compound accumulation in Gram-negative bacteria. In general, for a compound to accumulate in Gram-negative bacteria, it must possess an ionizable nitrogen, be relatively flat, and rigid. A major hurdle to this approach is installation of the nitrogen without disturbing target engagement. A solution to this involves appendage of ionizable nitrogens on a prodrug moiety such that it crosses the outer membrane and is cleaved within Gram-negative bacteria, releasing the active antibiotic. Such novel strategy can be a powerful approach to combat disease-causing pathogens as it addresses the major limitation of discovering new broad-spectrum antibiotics: passage across the outer membrane, and ultimately accumulation. The chapters herein emphasize the importance of combating antibiotic resistance, specifically against Gram-negatives, and provide actionable strategies by which to accomplish this mission. Chapter 1 focuses on the challenges of generating Gram-negative actives and describes novel solutions to this problem. This chapter also describes the structure-activity relationship of Gram-positive only antibiotic fusidic acid. Chapter 2 discusses the ring distortion of the alkaloid sinomenine using the complexity-to-diversity (CtD) approach to generate 66 total compounds, which played a key role in identifying the 3-dimensionality parameter, globularity (Glob), as important for accumulation in Gram-negative bacteria, and eventual discovery of the eNTRy rules. Chapter 3 describes our initial efforts to convert fusidic acid using the eNTRy rules and then describes the success of this conversion target using a novel polyamine amidoxime ester prodrug strategy.

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

• Garcia, Alfredo

Contributors dc:contributor

• Hergenrother, Paul J.
• Mitchell, Douglas A.
• van der Donk, Wilfred A.
• Zimmerman, Steve C.

• Ring distortion
• sinomenine
• fusidic acid
• prodrug
• broad-spectrum antibiotic

Statement dc:rights

• Copyright 2019 Alfredo Garcia

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/105134

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/105134