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Characterization of the Interaction Between Drug-Like Fragments and the S. aureus Response Regulator AgrA and their Inhibitory Effects on Virulence Expression

by
Ian Bezar
BA, Cornell University, 2006

Thesis Advisor: Ann Stock, PHD

Wednesday, February 24, 2016
1:30 PM


Abstract

Staphylococcus aureus is a serious and pervasive human health threat. The pathogenic bacterium is the leading cause of soft tissue infections in both community acquired and nosocomial infections, and the bacteria`s prolific virulon promotes the formation of potentially life threatening invasive infections. Treatment of stapyhlococcal infections has become increasingly difficult due to the emergence and proliferation of strains resistant to many commonly employed antibiotics in the form of MRSA strains. The threat of the emergence of staphylococcal strains that are resistant to all known antibiotics looms largely as the spread of such antibiotic resistance among other bacterial species has already been observed, leading to a call for novel approaches for the design of antimicrobial agents.
The targeting of virulence activation for selective inhibition ha been proposed as a new line of attack for combating infection. As toxin production accounts for many of the harmful effects caused by infection, the inhibition of virulence expression would theoretically lead to attenuation of infections. This strategy has also been suggested to escape the pitfall of selection for resistance characteristic of more traditional antibiotics since virulence genes are often non-essential, although this notion has been met with significant skepticism.
We have identified five drug-like compound fragments that target AgrA, the transcriptional activator of virulence expression in S. aureus. The interaction of the compounds with the LytTR DNA-binding domain of AgrA has been characterized using insight from structural and computational studies. Analysis of the affinity and activity of several of the compounds have been examined using in vitro assays. The compounds were also analyzed in several cell based assays for their ability to inhibit known function of the agr system including transcriptional regulation, toxin production, and biofilm formation. Our results suggest that the identified compounds would make for useful tools in studies seeking to determine the validity of targeting virulence expression for therapeutic purposes, and could even serve as starting points for the design of more effective inhibitors.


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