Document Type

Dissertation

Degree

Doctor of Philosophy

Major

Chemistry

Date of Defense

4-29-2022

Graduate Advisor

Dr George W. Gokel

Committee

Dr Eike Bauer

Dr Chung Wong

Dr Bruce Hamper

Abstract

Amphiphiles play important roles in nature. These molecules contain both hydrophilic and hydrophobic regions, leading to some astonishing properties. The lipid bilayer of the cell membrane is a fascinating organization of amphiphilic phospholipids. Natural and synthetic amphiphiles, such as antimicrobial peptides, interact with the cell membrane. Such interactions can impact transport of molecules across the cell membrane, disrupting cell functions. In this work, a library of tryptophan-containing amphiphiles was synthesized and their antimicrobial properties were explored.

First, a library of bis(tryptophan) amphiphiles was synthesized. Preparation included a coupling reaction of a diamine with tryptophan residues, via their carboxy-termini, at either end. The carbon chain length of the diamine was varied to yield bis(tryptophan) amphiphiles of varying lengths. Traditional methods of characterization were used to confirm identification of the compounds synthesized.

Second, the antimicrobial activity of the bis(tryptophan) amphiphiles was explored. Minimum inhibitory concentrations were determined for each of the amphiphiles against three bacterial strains. E. coli (K-12) was used for the initial screening, followed by a methicillin-resistant S. aureus (MRSA) strain and then a multi-drug resistant (MDR) strain of E. coli. Biological activity was observed for four of the amphiphiles in the micromolar range.

Third, characterization of the properties of the bis(tryptophan) amphiphiles was conducted. Dynamic light scattering studies showed that some of the amphiphiles formed aggregates in phosphate buffered saline solution. The amphiphiles that did not form aggregates were also not biologically active against the three bacterial strains. Scanning electron microscopy confirmed the presence of spherical aggregates > 1000 nm in diameter.

This work has allowed for the development of more potent bis(tryptophan) amphiphiles. It has shown their ability to form aggregates in saline solution and demonstrated a link between antimicrobial activity and aggregate formation.

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