Substituted Diphenyl Ethers as a Novel Chemotherapeutic Platform against Burkholderia pseudomallei
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 inBurkholderiais 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 inBurkholderia 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 theB. 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 aBurkholderia ex vivoefficacy model, and two demonstrated efficacy in an acuteB. 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.