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: 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
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 58 Issue 3 Pg. 1646-51 ( 2014) ISSN: 1098-6596 [Electronic] United States
• PMID: 24379198 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Anti-Bacterial Agents
• Phenyl Ethers
• Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)

Topics

• Animals
• Anti-Bacterial Agents (pharmacology)
• Burkholderia pseudomallei (drug effects, enzymology)
• Disease Models, Animal
• Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) (antagonists & inhibitors, metabolism)
• Female
• Melioidosis (drug therapy)
• Mice
• Mice, Inbred BALB C
• Microbial Sensitivity Tests
• Phenyl Ethers (pharmacology)
• Vero Cells (drug effects)