Serendipitous discovery of two highly selective inhibitors of bacterial luciferase

Herein, we report the serendipitous discovery of two highly selective inhibitors of bacterial luciferase, N-phenacylthiazolium bromide (PTB) and pifithrin-α (PFT-α). These compounds, which are both derivatives of N-phenacylthiazolium salts, comprise a previously unreported class of luciferase inhibitors that are effective both in vitro and in live bacteria. Interestingly, although they are structurally similar, these compounds appear to elicit inhibitory effects via two different modes of action. Support for these conclusions has been obtained using purified luciferase enzyme as well as genetic knockout strains of Vibrio harveyi. Overall, this report provides the first evidence that N-phenacylthiazolium derivatives can serve as luciferase inhibitors, and also illustrates how the systematic investigation of logical hypotheses can lead to unexpected and potentially useful outcomes.