Steiner Olivia M, Johnson Rachel A, Chen Xiaoyan, Simke William C, Li Bo
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
Biochemistry. 2025 Jan 7;64(1):192-202. doi: 10.1021/acs.biochem.4c00533. Epub 2024 Dec 12.
Dithiolopyrrolone (DTP) natural products are broad-spectrum antimicrobial and anticancer prodrugs. The DTP structure contains a unique bicyclic ene-disulfide that once reduced in the cell, chelates metal ions and disrupts metal homeostasis. In this work we investigate the intracellular activation of the DTPs and their resistance mechanisms in bacteria. We show that the prototypical DTP holomycin is reduced by several bacterial reductases and small-molecule thiols in vitro. To understand how bacteria develop resistance to the DTPs, we generate mutants that exhibit increased resistance to the hybrid DTP antibiotic thiomarinol. From these mutants we identify loss-of-function mutations in redox genes that are involved in DTP activation. This work advances the understanding of how DTPs are activated and informs development of bioreductive disulfide prodrugs.
二硫代吡咯烷酮（DTP）天然产物是广谱抗菌和抗癌前药。DTP结构包含一个独特的双环烯二硫化物，一旦在细胞中被还原，就会螯合金属离子并破坏金属稳态。在这项工作中，我们研究了DTPs在细菌中的细胞内激活及其耐药机制。我们表明，原型DTP全霉素在体外可被几种细菌还原酶和小分子硫醇还原。为了了解细菌如何对DTPs产生耐药性，我们生成了对杂交DTP抗生素硫代马林醇具有增强耐药性的突变体。从这些突变体中，我们鉴定出参与DTP激活的氧化还原基因中的功能丧失突变。这项工作推进了对DTPs如何被激活的理解，并为生物还原二硫化物前药的开发提供了信息。
