Francisella tularensis is classified as a category A priority pathogen and causes fatal disseminated disease in humans upon inhalation of less than 50 bacteria. Although drugs are available for treatment, they are not ideal because of toxicity and route of delivery, and in some cases patients relapse upon withdrawal. We have an ongoing program to develop novel FAS-II FabI enoyl-ACP
reductase enzyme inhibitors for Francisella and other select agents. To establish F. tularensis FabI (FtFabI) as a clinically relevant
drug target, we demonstrated that
fatty acid biosynthesis and FabI activity are essential for growth even in the presence of exogenous long-chain
lipids and that FtfabI is not transcriptionally altered in the presence of exogenous long-chain
lipids. Inhibition of FtFabI or
fatty acid synthesis results in loss of viability that is not rescued by exogenous long-chain
lipid supplementation. Importantly, whole-genome transcriptional profiling of F. tularensis with
DNA microarrays from infected tissues revealed that FtfabI and de novo
fatty acid biosynthetic genes are transcriptionally active during
infection. This is the first demonstration that the FabI enoyl-ACP-
reductase enzyme encoded by F. tularensis is essential and not bypassed by exogenous
fatty acids and that de novo
fatty acid biosynthetic components encoded in F. tularensis are transcriptionally active during
infection in the mouse model of
tularemia.