%0 Journal Article %J Chem Biol %D 2014 %T Metal-induced isomerization yields an intracellular chelator that disrupts bacterial iron homeostasis. %A Falconer, Shannon B %A Wang, Wenliang %A Gehrke, Sebastian S %A Cuneo, Jessica D %A Britten, James F %A Wright, Gerard D %A Brown, Eric D %K Anti-Bacterial Agents %K Bacterial Proteins %K Benzopyrans %K Crystallography, X-Ray %K Dose-Response Relationship, Drug %K Drug Evaluation, Preclinical %K Escherichia coli %K High-Throughput Screening Assays %K Homeostasis %K Indoles %K Iron %K Iron Chelating Agents %K Organometallic Compounds %K Small Molecule Libraries %K Spiro Compounds %K Stereoisomerism %K Structure-Activity Relationship %K Thiadiazoles %K Transcription Factors %K Transition Elements %X

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.

%B Chem Biol %V 21 %P 136-45 %8 2014 Jan 16 %G eng %N 1 %R 10.1016/j.chembiol.2013.11.007