Dithiolopyrrolones Are Prochelators That Are Activated by Glutathione

Dithiolopyrrolones (DTPs), such as holomycin, are natural products that hold promise as scaffolds for antibiotics as they exhibit inhibitory activity against antibiotic-resistant pathogens. They consist of a unique bicyclic core containing a disulfide that is crucial for their biological activity. Herein, we establish the DTPs as prochelators. We show that the disulfides are reduced at cellular gluathione levels. This activates the drugs and initiates interactions with targets, particularly metal coordination. In addition, we report an expedient synthesis for the DTPs thiolutin and aureothricin, providing facile access to important natural DTPs and derivatives thereof.