Substituted diphenyl ethers as a novel chemotherapeutic platform against Burkholderia pseudomallei

Jason E. Cummings, Adam J. Beaupre, Susan E. Knudson, Nina Liu, Weixuan Yu, Carla Neckles, Hui Wang, Avinash Khanna, Gopal R. Bommineni, Lily A. Trunck, Herbert P. Schweizer, Peter J. Tonge, Richard A. Slayden

Research output: Contribution to journalArticle

10 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1646-1651
Number of pages6
JournalAntimicrobial Agents and Chemotherapy
Volume58
Issue number3
DOIs
StatePublished - Mar 1 2014

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ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Cummings, J. E., Beaupre, A. J., Knudson, S. E., Liu, N., Yu, W., Neckles, C., Wang, H., Khanna, A., Bommineni, G. R., Trunck, L. A., Schweizer, H. P., Tonge, P. J., & Slayden, R. A. (2014). Substituted diphenyl ethers as a novel chemotherapeutic platform against Burkholderia pseudomallei. Antimicrobial Agents and Chemotherapy, 58(3), 1646-1651. https://doi.org/10.1128/AAC.02296-13