Small molecule inhibitors of anthrax edema factor

Bioorg Med Chem Lett. 2018 Jan 15;28(2):134-139. doi: 10.1016/j.bmcl.2017.11.040. Epub 2017 Nov 24.

Abstract

Anthrax is a highly lethal disease caused by the Gram-(+) bacteria Bacillus anthracis. Edema toxin (ET) is a major contributor to the pathogenesis of disease in humans exposed to B. anthracis. ET is a bipartite toxin composed of two proteins secreted by the vegetative bacteria, edema factor (EF) and protective antigen (PA). Our work towards identifying a small molecule inhibitor of anthrax edema factor is the subject of this letter. First we demonstrate that the small molecule probe 5'-Fluorosulfonylbenzoyl 5'-adenosine (FSBA) reacts irreversibly with EF and blocks enzymatic activity. We then show that the adenosine portion of FSBA can be replaced to provide more drug-like molecules which are up to 1000-fold more potent against EF relative to FSBA, display low cross reactivity when tested against a panel of kinases, and are nanomolar inhibitors of EF in a cell-based assay of cAMP production.

Keywords: Anthrax; Covalent inhibitor; Edema factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anthrax / drug therapy*
  • Antigens, Bacterial / pharmacology
  • Bacillus anthracis / drug effects*
  • Bacterial Toxins / antagonists & inhibitors*
  • Bacterial Toxins / pharmacology
  • Cyclic AMP / antagonists & inhibitors
  • Cyclic AMP / biosynthesis
  • Dose-Response Relationship, Drug
  • Humans
  • Mice
  • Molecular Structure
  • Protein Kinases / metabolism
  • RAW 264.7 Cells
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antigens, Bacterial
  • Bacterial Toxins
  • Small Molecule Libraries
  • anthrax toxin
  • Cyclic AMP
  • Protein Kinases