Identification and Characterization of Compounds with Inhibitory Properties towards Salmonella enterica Biofilms
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Date
2016-12
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Publisher
The Ohio State University
Abstract
Salmonella enterica serovar Typhi (S. Typhi), the causative agent of Typhoid Fever in humans, persists in the gallbladder of 3-5% of hosts after resolution of acute infection. In this chronic carrier state, S. Typhi forms biofilms on the surface of gallstones. This study utilized a screen of 90 kinase inhibitor compounds for in vitro anti-biofilm activity against a model organism, Salmonella enterica serovar Typhimurium (S. Typhimurium), and further characterized a promising lead: T315. T315 has anti-cancer properties and has been demonstrated to disrupt the PI3K/AKT pathway, which contributes to cancer progression. The effects of T315 on S. Typhimurium biofilm formation were analyzed using rapid attachment, viability, EC50, and biofilm dispersion assays. The compound does not exhibit bactericidal activity against S. Typhimurium, yet inhibits biofilm formation by 59.4 percent, with an EC50 of 4.61 μM. Delaying drug administration permitted assessment of biofilm inhibitory activity at varying timepoints and showed that the compound interferes specifically with the earliest stages of bacterial surface attachment. T315 is being derivatized and these compounds will be screened to identify those with a lower EC50. Additionally, we are identifying the bacterial target of this compound via direct pull-down with T315 that has been biotinylated using click-chemistry. The discovery and characterization of compounds with the ability to specifically inhibit early events in bacterial attachment will aid future studies of Salmonella biofilm formation and is a promising step towards eradication of the Salmonella chronic carriage state.
Description
First Place, Denman Undergraduate Research Forum
Keywords
biofilm, pathogenesis, bacteria, salmonella