title: The Burkholderia pseudomallei enoyl-acyl carrier protein reductase FabI1 is essential for in vivo growth and is the target of a novel chemotherapeutic with efficacy.
abstract: The bacterial fatty acid biosynthesis pathway is a validated target for the development of novel chemotherapeutics. However, since Burkholderia pseudomallei carries genes that encode both FabI and FabV enoyl-acyl carrier protein (ACP) reductase homologues, the enoyl-ACP reductase that is essential for in vivo growth needs to be defined so that the correct drug target can be chosen for development. Accordingly, ΔfabI1, ΔfabI2, and ΔfabV knockout strains were constructed and tested in a mouse model of infection. Mice infected with a ΔfabI1 strain did not show signs of morbidity, mortality, or dissemination after 30 days of infection compared to the wild-type and ΔfabI2 and ΔfabV mutant strains that had times to mortality of 60 to 84 h. Although signs of morbidity and mortality of ΔfabI2 and ΔfabV strains were not significantly different from those of the wild-type strain, a slight delay was observed. A FabI1-specific inhibitor was used to confirm that inhibition of FabI1 results in reduced bacterial burden and efficacy in an acute B. pseudomallei murine model of infection. This work establishes that FabI1 is required for growth of Burkholderia pseudomallei in vivo and is a potential molecular target for drug development.
authors.affiliation: Rocky Mountain Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research and Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Cummings
authors.forename: Luke C
authors.initials: LC
authors.lastname: Kingry
authors.forename: Drew A
authors.initials: DA
authors.lastname: Rholl
authors.forename: Herbert P
authors.initials: HP
authors.lastname: Schweizer
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Tonge
authors.forename: Richard A
authors.initials: RA
authors.lastname: Slayden
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D016957:Burkholderia pseudomallei / Q000187:drug effects / Q000201:enzymology / Q000235:genetics* / Q000472:pathogenicity; D050745:Enoyl-(Acyl-Carrier Protein) Reductase (NADPH, B-Specific) / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D055786:Gene Knockout Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008554:Melioidosis / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D051379:Mice; D009154:Mutation; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D050745:Enoyl-(Acyl-Carrier Protein) Reductase (NADPH, B-Specific)