title: Substituted diphenyl ethers as a novel chemotherapeutic platform against Burkholderia pseudomallei.
abstract: Identification of a novel class of anti-Burkholderia compounds is key in addressing antimicrobial resistance to current therapies as well as naturally occurring resistance. The FabI enoyl-ACP reductase in Burkholderia is an underexploited target that presents an opportunity for development of a new class of inhibitors. A library of substituted diphenyl ethers was used to identify FabI1-specific inhibitors for assessment in Burkholderia pseudomallei ex vivo and murine efficacy models. Active FabI1 inhibitors were identified in a two-stage format consisting of percent inhibition screening and MIC determination by the broth microdilution method. Each compound was evaluated against the B. pseudomallei 1026b (efflux-proficient) and Bp400 (efflux-compromised) strains. In vitro screening identified candidate substituted diphenyl ethers that exhibited MICs of less than 1 μg/ml, and enzyme kinetic assays were used to assess potency and specificity against the FabI1 enzyme. These compounds demonstrated activity in a Burkholderia ex vivo efficacy model, and two demonstrated efficacy in an acute B. pseudomallei mouse infection model. This work establishes substituted diphenyl ethers as a suitable platform for development of novel anti-Burkholderia compounds that can be used for treatment of melioidosis.
authors.affiliation: 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: Adam J
authors.initials: AJ
authors.lastname: Beaupre
authors.forename: Susan E
authors.initials: SE
authors.lastname: Knudson
authors.forename: Nina
authors.initials: N
authors.lastname: Liu
authors.forename: Weixuan
authors.initials: W
authors.lastname: Yu
authors.forename: Carla
authors.initials: C
authors.lastname: Neckles
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Avinash
authors.initials: A
authors.lastname: Khanna
authors.forename: Gopal R
authors.initials: GR
authors.lastname: Bommineni
authors.forename: Lily A
authors.initials: LA
authors.lastname: Trunck
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 / Q000494:pharmacology*; D016957:Burkholderia pseudomallei / Q000187:drug effects* / Q000201:enzymology; D004195:Disease Models, Animal; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D008554:Melioidosis / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D010647:Phenyl Ethers / Q000494:pharmacology*; D014709:Vero Cells / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D010647:Phenyl Ethers; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)