Discovery of Prenyltransferase Inhibitors with and Antibacterial Activity.

-prenyltransferases such as undecaprenyl diphosphate synthase (UPPS) and decaprenyl diphosphate synthase (DPPS) are essential enzymes in bacteria and are involved in cell wall biosynthesis. UPPS and DPPS are absent in the human genome, so they are of interest as targets for antibiotic development. Here, we screened a library of 750 compounds from National Cancer Institute Diversity Set V for the inhibition of DPPS and found 17 hits, and then ICs were determined using dose-response curves. Compounds were tested for growth inhibition against a panel of bacteria, for activity in a / model, and for mammalian cell toxicity. The most active DPPS inhibitor was the dicarboxylic acid redoxal (compound ), which also inhibited undecaprenyl diphosphate synthase (UPPS) as well as farnesyl diphosphate synthase. was active against , , Sterne, and , and there was a 3.4-fold increase in IC on addition of a rescue agent, undecaprenyl monophosphate. We found that was also a weak protonophore uncoupler, leading to the idea that it targets both isoprenoid biosynthesis and the proton motive force. In an / model, reduced the burden 3 times more effectively than did ampicillin.