Discovery of an Inhibitor for Bacterial 3-Mercaptopyruvate Sulfurtransferase that Synergistically Controls Bacterial Survival

Giorgia Croppi; Yueyang Zhou; Rong Yang; Yunfei Bian; Mingtao Zhao; Youtian Hu; Benfang Helen Ruan; Jing Yu; Fang Wu

doi:10.1016/j.chembiol.2020.10.012

Discovery of an Inhibitor for Bacterial 3-Mercaptopyruvate Sulfurtransferase that Synergistically Controls Bacterial Survival

Cell Chem Biol. 2020 Dec 17;27(12):1483-1499.e9. doi: 10.1016/j.chembiol.2020.10.012. Epub 2020 Nov 12.

Authors

Giorgia Croppi¹, Yueyang Zhou¹, Rong Yang¹, Yunfei Bian², Mingtao Zhao³, Youtian Hu¹, Benfang Helen Ruan², Jing Yu⁴, Fang Wu⁵

Affiliations

¹ Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China.
² College of Pharmaceutical Science, Collaborative Innovation Center of Yangtza River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, China.
³ State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
⁴ State Key Laboratory of Microbial Metabolism, Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China. Electronic address: jingyu@sjtu.edu.cn.
⁵ Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China. Electronic address: fang.wu@sjtu.edu.cn.

PMID: 33186540
DOI: 10.1016/j.chembiol.2020.10.012

Abstract

H₂S-producing enzymes in bacteria have been shown to be closely engaged in the process of microbial survival and antibiotic resistance. However, no inhibitors have been discovered for these enzymes, e.g., 3-mercaptopyruvate sulfurtransferase (MST). In the present study, we identified several classes of inhibitors for Escherichia coli MST (eMST) through high-throughput screening of ∼26,000 compounds. The thiazolidinedione-type inhibitors were found to selectively bind to Arg178 and Ser239 residues of eMST but hardly affected human MST. Moreover, the pioglitazone of this class concentration dependently accumulates the 3-mercaptopyruvate substrate and suppresses the H₂S and reactive sulfane sulfur products in bacteria. Importantly, pioglitazone could potentiate the level of reactive oxygen species in cellulo and consequently enhance the antimicrobial effects of gentamicin and macrophages in culture. This study has identified the bioactive inhibitor of eMST, paving the way for the pharmacological targeting of eMST to synergistically control the survival of E. coli.

Keywords: 3-mercaptopyruvate sulfurtransferase; CRISPR-Cas9; Escherichia coli; ROS; antibiotic resistance; hydrogen sulfide; oxidative stress; pioglitazone; roGFP2; synergy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Drug Design*
Drug Evaluation, Preclinical
Drug Synergism
Enzyme Inhibitors / pharmacology*
Escherichia coli / drug effects*
Escherichia coli / enzymology*
Escherichia coli / physiology
High-Throughput Screening Assays
Humans
Sulfurtransferases / antagonists & inhibitors*

Substances

Enzyme Inhibitors
Sulfurtransferases
3-mercaptopyruvate sulphurtransferase