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

Chemistry & Biology
Shannon B FalconerEric D Brown

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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Citations

Jun 24, 2015·Annals of the New York Academy of Sciences·Maya A Farha, Eric D Brown
Oct 27, 2016·Physical Chemistry Chemical Physics : PCCP·Jérôme F L DuvalElise Rotureau
Jan 8, 2020·Antimicrobial Agents and Chemotherapy·Derek C K ChanLori L Burrows
Apr 1, 2021·Accounts of Chemical Research·Maya A FarhaEric D Brown
Jul 6, 2021·European Journal of Medicinal Chemistry·Ting WangJianyou Shi
Mar 21, 2018·ACS Infectious Diseases·Jacqueline M Zaengle-BaroneKatherine J Franz
Nov 14, 2018·ACS Infectious Diseases·Pasquale LincianoDonatella Tondi

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