Inhibitors of quorum-sensing affect Bacillus anthracis growth and virulence gene expression

Jones M.B., Ren, D., Wood, T., and Blaser, M.J.

Density-dependent gene expression, quorum-sensing (Q-S), involves the synthesis and detection of small molecular weight molecules known as auto-inducers. The identification of inhibitors of bacterial Q-S systems offers a novel means of treating highly virulent, or multi-drug resistant infections, and to identify genes regulated by Q-S. A novel furanone compound isolated from the marine alga, Delisea pulchra, is a potent inhibitor of bacterial Q-S systems, including those of Pseudomonas aeruginosa and Erwinia carotovora. Bacillus anthracis, the etiological agent of anthrax, possesses genes involved in Q-S. With the emergence of B. anthracis spores as a weapon of terror, it is essential to develop new therapies for anthrax. In the present study, we utilized the naturally synthesized Q-S inhibitor (5Z)-4-bromo-5-(bromomethylene)-3-butyl-2(5H)-furanone [fur-1], as well as chemical derivatives (fur-2 and fur-4) of fur-1, to examine the effects on B. anthracis growth and protective antigen gene (pagA) expression. B. anthracis Sterne strain has a significant growth defect in the presence of fur-1, 2 and 4 in a dose-dependent manner with >24-hr inhibition at doses ³ 20 mg/ml; fur-4 had the greatest inhibitory effect. When fur-1 was added to cultures of B. anthracis strain RABF140 (pagA-lacZ) in mid-log phase, growth was inhibited in a dose-dependent manner, and in addition, pagA expression, as measured by the LacZ reporter, was inhibited to a proportionately greater extent. These data suggest that the use of Q-S inhibitors might represent a novel therapy for anthrax.