Identification of a lead small-molecule inhibitor of anthrax lethal toxin by using fluorescence-based high-throughput screening.

Inhalational anthrax is caused by B. anthracis, a virulent spore-forming bacterium which secretes anthrax toxins consisting of protective antigen (PA), lethal factor (IF) and edema factor (EF). LF is a Zn-dependent metalloprotease and is the main determinant in the pathogenesis of anthrax. Here we report the identification of a lead small-molecule inhibitor of anthrax lethal factor by screening an available synthetic small-molecule inhibitor library using fluorescence-based high-throughput screening (HIS) approach. Seven small molecules were found to have inhibitory effect against IF activity, among which SM157 had the highest inhibitory activity. All theses small molecule inhibitors inhibited IS in a noncompetitive inhibition mode. SM157 and SM167 are from the same family, both having an identical group complex, which is predicted to insert into S1' pocket of LE. More potent small-molecule inhibitors could be developed by modifying SM157 based on this identical group complex. [BMB reports 2011; 44(12): 811-815]