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

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Abstract

Summary 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. © 2014 Elsevier Ltd.

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Falconer, S. B., Wang, W., Gehrke, S. S., Cuneo, J. D., Britten, J. F., Wright, G. D., & Brown, E. D. (2014). Metal-induced isomerization yields an intracellular chelator that disrupts bacterial iron homeostasis. Chemistry and Biology, 21(1), 136–145. https://doi.org/10.1016/j.chembiol.2013.11.007

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