Biomedical Sciences ETDs

Author

Erin Sully

Publication Date

7-1-2011

Abstract

The increasing emergence of antibiotic resistant Staphylococcus aureus infections, particularly those caused by a single clone of methicillin resistant S. aureus (USA300 MRSA), coupled with the slowing of antibiotic discovery makes research into novel therapies a priority (Lowy, 2007). One strategy evolving is the development of drugs that target bacterial virulence factors as opposed to growth (Cegelski et al., 2008). Due to the lack of selective pressure, bacterial resistance to the drugs would be minimized while the infection, attenuated by the inhibition of virulence factor production, could be cleared by the innate immune factors of the host. Virulence factors identified to date as essential for invasive USA 300 MRSA infection are globally regulated in part by a quorum sensing operon, agr (George and Muir, 2007; Novick and Geisinger, 2008; Yarwood and Schlievert, 2003). Host factors like apolipoprotein B provide defense by antagonizing agr signaling which demonstrates that host defense against an invasive infection could be accomplished by blocking agr signaling (Peterson et al., 2008). Therefore, we hypothesized that screening small molecule inhibitors for inhibition of agr signaling could contribute to drug discovery by providing optimal host defense against quorum sensing dependent S. aureus infections. Our work focuses on two small molecule inhibitors, CID# 2333 and CID# 3243271, identified in a screen of over 20,000 compounds for antagonism of agr signaling. These compounds demonstrate virulence factor inhibition in vitro and in an in vivo model of community associated -MRSA dermonecrotic infection.

Keywords

CA-MRSA, staphylococcus aureus, small molecule inhibitor, high-throughput screen, virulence, quorum sensing

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Advisor

Gresham, Hattie

First Committee Member (Chair)

Gresham, Hattie

Second Committee Member

Hall, Pamela

Third Committee Member

Mold, Carolyn

Fourth Committee Member

Ozbun, Michelle

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