Document Type

Dissertation

Degree

Doctor of Philosophy

Major

Chemistry

Date of Defense

7-15-2025

Graduate Advisor

Prof. Keith J. Stine

Committee

Prof. Alexei V. Demchenko, PhD

Prof. Michael R. Nichols, PhD

Prof. Chung F. Wong, PhD

Abstract

Lipopolysaccharide (LPS), a key structural component of Gram-negative bacteria, is a major trigger of sepsis and septic shock, the systemic inflammatory conditions responsible for millions of deaths annually. Even at concentrations as low as 1 ng/mL, LPS can activate the immune system and initiate inflammatory cascades. According to the Global Burden of Disease Study 2017, sepsis accounted for 48.9 million cases globally, with 11 million deaths, emphasizing the urgent need for improved diagnostic and therapeutic strategies.

Accurate and rapid detection of LPS is vital for early intervention and improved clinical outcomes. While traditional detection methods are still widely used, modern biosensing technologies, particularly those employing nanomaterials, offer significant advantages in sensitivity and selectivity. Among these, nanoporous gold nanoparticles (np-AuNPs) are especially promising due to their high surface area, chemical stability, biocompatibility, and ease of surface modification. In this study, we report a simple, solution-phase synthesis of colloidal np-AuNPs via a wet chemical approach. These nanostructures were subsequently utilized to construct a biosensing platform capable of detecting LPS with high sensitivity.

Beyond diagnostics, LPS research plays a crucial role in understanding immune system activation, inflammation, and bacterial pathogenesis. It is also implicated in various conditions, including autoimmune diseases and infections caused by Escherichia coli and Salmonella species. Furthermore, LPS contributes to antimicrobial resistance by acting as a permeability barrier in the outer membrane of Gram-negative bacteria, limiting antibiotic access. By examining how LPS structure and modifications (e.g., lipid additions or protein changes) affect drug resistance, researchers can identify new targets to overcome these defenses. Understanding LPS’s role in resistance mechanisms could help develop strategies to make bacteria more susceptible to existing antibiotics, improving treatment options and combating multidrug-resistant infections.

To investigate biophysical interactions of LPS at the molecular level, we employed model membrane systems, such as monolayers, which simulate biological membranes in a controlled setting. These platforms enabled detailed analysis of how LPS and potential LPS-antagonists engage with membrane lipids and proteins. In particular, we explored the interactions of LPS with various membrane-associated components and a potential LPS-antagonist, AM-12, offering insights into their interactions.

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