Activation of\nDithiolopyrrolone Antibiotics by Cellular\nReductants

Dithiolopyrrolone (DTP) natural products are broad-spectrum\nantimicrobial\nand anticancer prodrugs. The DTP structure contains a unique bicyclic\nene-disulfide that once reduced in the cell, chelates metal ions and\ndisrupts metal homeostasis. In this work we investigate the intracellular\nactivation of the DTPs and their resistance mechanisms in bacteria.\nWe show that the prototypical DTP holomycin is reduced by several\nbacterial reductases and small-molecule thiols in vitro. To understand\nhow bacteria develop resistance to the DTPs, we generate Staphylococcus aureus mutants that exhibit increased\nresistance to the hybrid DTP antibiotic thiomarinol. From these mutants\nwe identify loss-of-function mutations in redox genes that are involved\nin DTP activation. This work advances the understanding of how DTPs\nare activated and informs development of bioreductive disulfide prodrugs.