Substituted Diphenyl Ethers as a Novel Chemotherapeutic Platform against Burkholderia pseudomallei
- Resource Type
- Article
- Authors
- Cummings, Jason E.; Beaupre, Adam J.; Knudson, Susan E.; Liu, Nina; Yu, Weixuan; Neckles, Carla; Wang, Hui; Khanna, Avinash; Bommineni, Gopal R.; Trunck, Lily A.; Schweizer, Herbert P.; Tonge, Peter J.; Slayden, Richard A.
- Source
- Antimicrobial Agents and Chemotherapy; February 2014, Vol. 58 Issue: 3 p1646-1651, 6p
- Subject
- Language
- ISSN
- 00664804; 10986596
ABSTRACTIdentification of a novel class of anti-Burkholderiacompounds is key in addressing antimicrobial resistance to current therapies as well as naturally occurring resistance. The FabI enoyl-ACP reductase in Burkholderiais 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 vivoand 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. pseudomallei1026b (efflux-proficient) and Bp400 (efflux-compromised) strains. In vitroscreening 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 vivoefficacy model, and two demonstrated efficacy in an acute B. pseudomalleimouse infection model. This work establishes substituted diphenyl ethers as a suitable platform for development of novel anti-Burkholderiacompounds that can be used for treatment of melioidosis.