Metal-Induced Isomerization Yields an Intracellular Chelator that Disrupts Bacterial Iron Homeostasis

• Screening methodology identifies perturbants of bacterial iron homeostasis
• Transition-metal-triggered isomerization produces merocyanine chelator
• Merocyanine isomer is toxic to bacteria via intracellular Fe2+ chelation

SummaryThe 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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