title: The Francisella tularensis FabI enoyl-acyl carrier protein reductase gene is essential to bacterial viability and is expressed during infection.
abstract: 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.
authors.affiliation: Rocky Mountain Regional Center of Excellence, Fort Collins, CO, USA.
authors.forename: Luke C
authors.initials: LC
authors.lastname: Kingry
authors.forename: Jason E
authors.initials: JE
authors.lastname: Cummings
authors.forename: Kerry W
authors.initials: KW
authors.lastname: Brookman
authors.forename: Gopal R
authors.initials: GR
authors.lastname: Bommineni
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Tonge
authors.forename: Richard A
authors.initials: RA
authors.lastname: Slayden
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000096:biosynthesis* / Q000235:genetics; D005227:Fatty Acids / Q000096:biosynthesis; D005604:Francisella tularensis / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development; D020869:Gene Expression Profiling; D015964:Gene Expression Regulation, Bacterial; D005798:Genes, Bacterial; D020043:Genes, Essential; D006801:Humans; D051379:Mice; D046228:Microarray Analysis; D050296:Microbial Viability; D020411:Oligonucleotide Array Sequence Analysis; D014406:Tularemia / Q000382:microbiology*
chemical_list: D005227:Fatty Acids; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)