Date of Award:

12-2025

Document Type:

Dissertation

Degree Name:

Doctor of Philosophy (PhD)

Department:

Chemistry and Biochemistry

Committee Chair(s)

Nicholas E. Dickenson

Committee

Nicholas E. Dickenson

Committee

Joan M. Hevel

Committee

Sean J. Johnson

Committee

Lance C. Seefeldt

Committee

Greg Podgorski

Abstract

The rise of antibiotic resistance is a growing global health crisis, with projections suggesting that by 2050 it could cost the world between $300 billion and $1 trillion annually. This alarming trend is caused by bacteria evolving survival strategies against commonly used antibiotics. The scientific community hopes to resolve these challenges by researching the systems that cause bacterial disease. The Type Three Secretion System (T3SS) is one of these systems and is a high priority due to its occurrence in multiple disease-causing bacteria. An understanding of how the T3SS works could help us find new ways to treat infections caused by antibiotic-resistant bacteria. The T3SS functions like a microscopic syringe. It is embedded in the bacteria and is used to inject proteins into host cells that facilitate bacterial disease. Although many types of bacteria have a T3SS, different species have evolved unique ways of using it to infect specific bodily systems. For example, Shigella uses its T3SS to attack the digestive system, leading to diarrhea, while Yersinia uses it to attack the immune system, causing diseases like the plague. For this versatility, each bacterial species T3SS has evolved in unique ways specific to the tissues where it causes disease. This research focuses on how the T3SS is controlled in different bacterial species and environments. A natural digestive chemical in the small intestine can make Shigella more infectious by activating the type three secretion system T3SS. In this study, we identified a specific structural feature, in the T3SS tip protein IpaD, that facilitates this digestive chemical infectious enhancing effect. We also studied the T3SS of Yersinia, the bacteria responsible for the black plague. Yersinia’s type three secretion system (T3SS) is powered by the protein YscN, which harnesses the energy required for T3SS function. We determined the structure of YscN using high resolution techniques and identified acidity and temperature the conditions for robust YscN function. Additionally, we tested chemicals that block function of a similar protein in Shigella and found that most were ineffective against YscN. However, one inhibitor demonstrated activity against both enzymes, suggesting its potential as a broad-spectrum treatment. These differences in inhibitor effectiveness underscore the importance of studying each species’ T3SS individually. We also investigated the T3SS in Salmonella, a common cause of food poisoning. Because Salmonella’s T3SS is closely related to Shigella’s and shares key features that allow it to sense environmental signals, we examined how both bacteria respond to these signals. This study highlights the differences between the related systems, as signal exposure caused opposite effects in each bacterial species. In summary, this research offers a detailed look at the structure and regulation of the T3SS in several pathogenic bacteria. It uncovers important new information critical to understanding T3SS function. By understanding how this system operates and species-specific environmental adaptations, we are one step closer to finding effective strategies for combatting the T3SS of pathogenic bacteria.

Checksum

0038410230f67d0527a90b6712093697

Download

Available for download on Sunday, December 01, 2030

Share

COinS

Copyright for this work is retained by the student. If you have any questions regarding the inclusion of this work in the Digital Commons, please email us at .