Dissertation
Regulatory mechanisms of the Staphylococcus aureus SrrAB two-component system
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Summer 2020
DOI: 10.17077/etd.005617
Abstract
Staphylococcus aureus infections lead to diseases ranging from skin abscess to life threatening toxic shock syndrome. Antibiotic resistant Staphylococcal aureus, commonly known as methicillin-resistant Staphylococcus aureus (MRSA) are the major cause of hospital infections in the United States. The antibiotic resistance of MRSA strains presents an urgent need of identifying novel therapeutics. Bacterial two-component systems (TCS) are signal transduction systems that allow bacteria to respond to their environments and contribute to infections by regulating toxin production, antibiotic resistance mechanisms and survival. Two-component systems are composed of membrane bound histidine kinase (HK) and cytoplasmic response regulator (RR). The HK senses extracellular ligand/stimuli through its extracellular sensor domain and undergoes autophosphorylation at a conserved histidine residue in the cytoplasmic kinase domain. The phosphorylated HK then transfers the phosphoryl group onto a conserved aspartate residue in the RR, which then binds DNA to control gene expression. The Staphyloccocal respiratory response AB (SrrAB) TCS is a global regulator of S. aureus virulence and critical for survival under the environmental conditions (hypoxia, oxidative and nitrosative stress) found at sites of infection. Despite the critical role of SrrAB in S. aureus pathogenicity, the signal(s) that SrrB histidine kinase senses and responds to, and the mechanism by which it is regulated remain unknown. The SrrB histidine kinase contains several domains, including an extracellular Cache domain, a transmembrane HAMP domain, intracellular PAS domain and DHp-CA catalytic region. Based on the findings of my thesis work, I propose a model whereby the SrrB histidine kinase senses and responds the cellular redox environment through heme-bound PAS domain and a disulfide in the CA domain to support S. aureus survival and pathogenesis.
Details
- Title: Subtitle
- Regulatory mechanisms of the Staphylococcus aureus SrrAB two-component system
- Creators
- Nitija Tiwari
- Contributors
- Ernesto J Fuentes (Advisor)Daniel L Weeks (Committee Member)Madeline A Shea (Committee Member)Todd M Washington (Committee Member)Catherine A Musselman (Committee Member)Craig D Ellermeier (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Biochemistry
- Date degree season
- Summer 2020
- DOI
- 10.17077/etd.005617
- Publisher
- University of Iowa
- Number of pages
- xiv, 194 pages
- Copyright
- Copyright 2020 Nitija Tiwari
- Language
- English
- Description illustrations
- illustrations (some color)
- Description bibliographic
- Includes bibliographical references (page 181-191).
- Public Abstract (ETD)
Staphylococcus aureus infections lead to life threatening diseases like infective endocarditis, osteomyelitis and sepsis. Over the years, antibacterial drugs like penicillin have been used to treat S. aureus infections. However, antibiotic resistant Staphylococcal aureus, commonly known as methicillin-resistant Staphylococcus aureus (MRSA) has become a major cause of hospital infections in the United States. This antibiotic resistance of MRSA strains presents an urgent need of identifying new antibacterial drugs. One of the ways to develop new antibacterial compounds is to target functions in bacteria that give them the ability to survive in human host, cause infection and fight with our immune system. The system that I investigated in my thesis-SrrAB two-component system is one of the many ways that S. aureus uses to turn into a pathogen and is critical for the bacteria’s survival at sites of infection. In this study, I identified how the SrrAB TCS functions. I showed that SrrAB controls TSST-1 production which causes toxic shock syndrome disease and biofilm formation. These findings show that SrrAB can be targeted to develop new antibacterial compounds.
- Academic Unit
- Biochemistry and Molecular Biology
- Record Identifier
- 9983988099602771
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