Oxidized glutathione reverts carbapenem resistance in bla NDM-1 -carrying Escherichia coli

• Published in: EMBO molecular medicine Vol. 16; no. 5; pp. 1051 - 1062
• Main Authors: Ye, Dongyang, Li, Xiaowei, Zhao, Liang, Liu, Saiwa, Jia, Xixi, Wang, Zhinan, Du, Jingjing, Ge, Lirui, Shen, Jianzhong, Xia, Xi
• Format: Journal Article
• Language: English
• Published: Germany Springer Nature 01.05.2024
• Subjects: Animals; Anti-Bacterial Agents - pharmacology; beta-Lactamases - genetics; beta-Lactamases - metabolism; Carbapenems; Carbapenems - pharmacology; Drug Resistance, Bacterial; Escherichia coli - drug effects; Escherichia coli - genetics; Escherichia coli Infections - drug therapy; Escherichia coli Infections - microbiology; Glutathione - metabolism; Humans; Metabolomics; Mice; Microbial Sensitivity Tests; NDM-1; Oxidation-Reduction - drug effects; Oxidized Glutathione; NDM-1; Metabolomics; Oxidized Glutathione; Carbapenems
• ISSN: 1757-4684
• DOI: 10.1038/s44321-024-00061-x

The emergence of drug-resistant Enterobacteriaceae carrying plasmid-mediated β-lactamase genes has become a significant threat to public health. Organisms in the Enterobacteriaceae family containing New Delhi metallo-β-lactamase‑1 (NDM-1) and its variants, which are capable of hydrolyzing nearly all β-lactam antibacterial agents, including carbapenems, are referred to as superbugs and distributed worldwide. Despite efforts over the past decade, the discovery of an NDM-1 inhibitor that can reach the clinic remains a challenge. Here, we identified oxidized glutathione (GSSG) as a metabolic biomarker for bla using a non-targeted metabolomics approach and demonstrated that GSSG supplementation could restore carbapenem susceptibility in Escherichia coli carrying bla in vitro and in vivo. We showed that exogenous GSSG promotes the bactericidal effects of carbapenems by interfering with intracellular redox homeostasis and inhibiting the expression of NDM-1 in drug-resistant E. coli. This study establishes a metabolomics-based strategy to potentiate metabolism-dependent antibiotic efficacy for the treatment of antibiotic-resistant bacteria.