Dissecting the Effects of (5Z)-4-Bromo-5-(bromomethylene)-3-Butyl-2-(5H)-Furanone on Bacillus Anthracis Metabolism

Quorum sensing inhibitors or quorum quenchers hold great potential as therapeutics for treating infectious diseases.  One such molecule, (5Z)-4-bromo-5-(bromomethylene)-3-butyl-2-(5H)-furanone (furanone) has been found to inhibit the quorum sensing circuit of Bacillus anthracis, the etiological agent of anthrax.  However, the impact of furanone on the cellular system as a whole remains unclear.  In this work, the affect of furanone on cellular metabolism was evaluated through an integrated analysis involving genome-scale metabolic modeling and experimental efforts.  Specifically, a metabolic model of B. anthracis consisting of 1,003 metabolites and 1,049 reactions was used to analyze experimental results collected for the Sterne strain of B. anthracis when grown in the presence of furanone.  It was found that although growth rate and glucose uptake rate both decreased in the presence of furanone, energy demand increased.  It was postulated that the higher energy requirement was necessary to accommodate critical energy-dependent translocation processes of key nutrients.  Additionally, the introduction of furanone appeared to alter the redox potential generation pathway, indicating that regeneration of NAD+ occurred by electron transfer to glycerol-3-phosphate rather than fermentation.  The overall impact appeared to be indicative of an oxidative stress response.