Inhibition of FabI in Fatty Acid Synthesis Pathway ‐ Novel Chemotherapeutics Against Francisella Tularensis

Abstract

Francisella tularensis is a highly virulent and contagious gram-negative intracellular bacterium that causes the disease tularemia in mammals. The high infectivity and the ability of the bacterium to survive for weeks in a cool, moist environment, have raised the possibility that this organism can be exploited deliberately as a potential biological weapon. Fatty acid synthesis (FAS) is essential for bacterial viability and it has also been validated as an attractive target for the discovery of novel antibacterials. Based on the result that there is a single enoyl reductase homologue in this bacterium, we hypothesize that this enzyme is a sensitive target for the development of novel antibiotics against tularemia. We have successfully cloned, overexpressed and purified the F. tularensis FabI (ftuFabI) and demonstrated that the gene encoded by FTT0782 is an enoyl reductase that catalyzes the NADH dependent reduction of enoyl-CoA substrates. We have solved the X-ray crystal structure of this protein to 2.5 ?resolution, and identified a series of diphenyl ethers which are nanomolar inhibitors of enzyme activity and that inhibit bacterial growth with MIC99 values as low as 0.2 ug/mL.