Metal-induced isomerization yields an intracellular chelator that disrupts bacterial iron homeostasis

  • Chem Biol. 2014 Jan 16;21(1):136-45. doi: 10.1016/j.chembiol.2013.11.007.
Shannon B Falconer  1 ,  Wenliang Wang  1 ,  Sebastian S Gehrke  1 ,  Jessica D Cuneo  1 ,  James F Britten  2 ,  Gerard D Wright  1 ,  Eric D Brown  3
Affiliations
  • 1. M.G. DeGroote Institute for Infectious Disease Research and Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.
  • 2. Department of Chemistry, McMaster University, Hamilton, ON L8S 4M1, Canada.
  • 3. M.G. DeGroote Institute for Infectious Disease Research and Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada. Electronic address: [email protected].
PMID: 24361049 DOI: 10.1016/j.chembiol.2013.11.007
Abstract

The dwindling supply of Antibiotics that remain effective against drug-resistant Bacterial pathogens has precipitated efforts to identify new compounds that inhibit Bacterial growth using untapped mechanisms of action. Here, we report both (1) a high-throughput screening methodology designed to discover chemical perturbants of the essential, yet unexploited, process of Bacterial iron homeostasis, and (2) our findings from a small-molecule screen of more than 30,000 diverse small molecules that led to the identification and characterization of two spiro-indoline-thiadiazoles that disrupt iron homeostasis in bacteria. We show that these compounds are intracellular chelators with the capacity to exist in two isomeric states. Notably, these spiroheterocyles undergo a transition to an open merocyanine chelating form with Antibacterial activity that is specifically induced in the presence of its transition-metal target.

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