Slow Onset Inhibitors Of Bacterial Fatty Acid Biosynthesis: Residence Time, In Vivo Activity And In Vivo Imaging

The goal of our structure‐based drug discovery effort is to develop slow onset enzyme inhibitors, based on the premise that the long residence time of the compounds on the target is critical for in vivo activity. Targets for drug resistant bacterial infections include the enoyl‐ACP reductase and β‐ketoacyl‐ACP synthase enzymes in the bacterial fatty acid biosynthesis pathway. We have developed slow onset diaryl‐ether inhibitors of the enoyl‐ACP reductases from Francisella tularensis and Mycobacterium tuberculosis and have shown that the in vivo antibacterial activity of the compounds in animal models of infection correlates with their residence time on the enzyme targets. We are exploring the mechanistic basis for slow onset inhibition and are using this information to develop inhibitors with longer residence times. We have also developed methods to introduce short‐lived isotopes into these compounds and are using the labeled molecules to identify the target(s) for the inhibitors in live cells and to image drug distribution in vivo .