Biomedical Sciences ETDs

Publication Date

7-1-2015

Abstract

Staphylococcus aureus is a global health threat due to its ability to cause significant morbidity and mortality and the exceptional capacity to acquire antibiotic resistance. One method to combat antibiotic resistance, proposed by the NIAID, is anti-virulence strategies focused on bacterial disarmament. S. aureus regulates over 200 virulence factors with the accessory gene regulator (agr) operon, which encodes a quorum sensing (QS) system, and many of the agr-regulated virulence factors are required for invasive infection. Therefore, we hypothesized that bacterial disarmament through the inhibition of agr quorum sensing will both complement immune function and mitigate the severity of S. aureus infection. First, in Chapter 2, we report the development and demonstrate the efficacy of the first active vaccine targeting the secreted signal of the agr system. The use of stable peptide mimotopes displayed with high valency on a virus-like particle proved successful in limiting agr-dependent pathogenesis in vivo, a significant advance in the field. Second, in Chapter 3, we utilize a novel natural product inhibitor of AgrA, ω-hydroxyemodin, to demonstrate that bacterial disarmament can both limit S. aureus pathogenesis and support host innate defense resulting in increased bacterial clearance. This is the first small molecule S. aureus QS inhibitor to demonstrate in vivo efficacy and a definitive mechanism of action. Both of the approaches demonstrate that inhibitors of QS would be efficacious as treatments to limit skin infections. Understanding the role of agr in other disease states such as pneumonia and bacteremia would enhance the clinical utility. Likewise, it will be essential to determine if QS inhibitors can function as adjunctive therapy to extend the clinical lifetime of current antibiotics. Inhibition of QS alone is not going to solve the antibiotic resistance crisis, but it is another tool that can be used to fight resistance.

Keywords

Staphylococcus aureus, Virulence, Quorum sensing, vaccine, virus-like particle, natural product

Sponsors

National Institutes of Health: AI091917, AI083305, AT007052, T32-AI007538, T32-AI007511 North Carolina Biotechnology Center Biotechnology Research Grant: 2011-BRG-1206

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Peabody, Dave

Second Committee Member

Chackerian, Bryce

Third Committee Member

Timmins, Graham

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