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Small molecule inhibition of Staphylococcus aureus virulence

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Please use this identifier to cite or link to this item: http://hdl.handle.net/1928/13173

Small molecule inhibition of Staphylococcus aureus virulence

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Title: Small molecule inhibition of Staphylococcus aureus virulence
Author: Sully, Erin
Advisor(s): Gresham, Hattie
Committee Member(s): Gresham, Hattie
Hall, Pamela
Mold, Carolyn
Ozbun, Michelle
Department: University of New Mexico. Biomedical Sciences Graduate Program
Subject(s): CA-MRSA
staphylococcus aureus
small molecule inhibitor
high-throughput screen
virulence
quorum sensing
LC Subject(s): Staphylococcus aureus infections--Prevention.
Virulence (Microbiology)--Molecular aspects.
Degree Level: Doctoral
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.
Graduation Date: July 2011
URI: http://hdl.handle.net/1928/13173

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