Date of Award

2025

Degree Name

Biomedical Research

College

Joan C. Edwards School of Medicine

Type of Degree

Ph.D.

Document Type

Dissertation

First Advisor

Dr. Hongwei Yu

Second Advisor

Dr. Eric Blough

Third Advisor

Dr. Timothy Long

Fourth Advisor

Dr. Lydia Bogomolnaya

Fifth Advisor

Dr. Meagan Valentine

Abstract

In a 2019 report by the Centers for Disease Control and Prevention (CDC), infections resistant to antibiotic treatment amount to about three million infections and 48,000 deaths. Antimicrobial resistance is an escalating global threat as existing antibiotics lose efficacy over time. The project described is focused on partnering with pharmaceutical researchers and producers to test new nanoparticle-based or repurposed compounds. The central hypothesis of this thesis is that pharmaceutical formulations such as nanoparticles may provide a cost-effective means of combating the emerging antimicrobial resistance. The nanoparticle compounds allowed for a wide range of customization for the pharmaceutical design, since the particle can be made from various materials including deoxyribose nucleic acid (DNA) and lipids (fats). Repurposing existing drugs can accelerate the transition from basic research to clinical application, leveraging established safety profiles. Both design of new drugs and repurposing can be used to help alleviate the growing resistance amongst deadly microbes. There were four areas of emphasis during this project. The first project focused on the testing of a DNA-nanoparticle peptide compound in a Bacillus anthracis Sterne strain pulmonary infection mouse model. The nanoparticle was a tetrahedron structure built from DNA particles with the antimicrobial peptide SMAP-29 attached. The peptide demonstrated promising in vitro results but failed to replicate these results in vivo. This project led to the second project on the expansion of information on the successful storage and use of B. anthracis Sterne strain for standard research laboratories. The bacterial strain lacks applicable information for pharmaceutical research at the level available to most academic institutions. Other strains, such as B. anthracis Ames strain, require higher safety levels, indicating that an increase in methodological information for Sterne strain could increase the amount of research being conducted on B. anthracis overall. During the third project, cannabidiolic acid (CBDA) and lipid-nanoparticles were used to treat acute lung inflammation in a mouse model. The lipid-nanoparticle was a collection of fats designed to form a protective shell around the CBDA particle. The compound decreased inflammatory signaling molecules and was comparable to high concentrations of the powerful steroid Dexamethasone, often used for severe inflammation in acute exacerbation of chronic obstructive pulmonary disease (AECOPD). The CBDA-nanoparticles were also found to have antimicrobial properties that could provide a promising avenue for addressing pulmonary infections by gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. The final project involved the repurposing and monitoring of disulfiram via analysis of the effect on the mouse gut microbiome. The compound has a similar structure to the antibiotic metronidazole with physicians warning of “disulfiram-like effects” when metronidazole is prescribed. It is also currently FDA approved for use as a sobriety aid which would fast-track approval for new uses considering the current safety profile. The live animal and laboratory results indicated an inhibitory effect towards select gram-positive pathogens, such as Staphylococcus aureus, while maintaining other anaerobe populations such as the probiotic Lactobacillus, potentially alleviating the intestinal discomfort associated with antimicrobial therapies. The data and interpretation of experiments in this document, which may be preliminary and require future validation, suggest alternative therapeutic strategies in combating antimicrobial resistance and avenues for future academic research on key pathogens of interest.

Subject(s)

Antibiotics.

Antibiotics -- Effectiveness.

Drug resistance in microorganisms.

Bacterial diseases -- Prevention.

Bacterial diseases -- Treatment.

Bacillus anthracis.

Cannabinoids.

Disulfiram.

Nanoparticles.

Drugs.

Staphylococcus -- Treatment.

DNA -- Medicine -- Treatment.

Lipids -- Medicine -- Treatment.

Peptides -- Medicine -- Treatment.

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