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 blaNDM-1 using a non-targeted metabolomics approach and demonstrated that GSSG supplementation could restore carbapenem susceptibility in Escherichia coli carrying blaNDM-1 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.

中文翻译：

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氧化型谷胱甘肽可恢复携带 blaNDM-1 的大肠杆菌中的碳青霉烯类耐药性。


携带质粒介导的β-内酰胺酶基因的耐药肠杆菌科细菌的出现已成为对公众健康的重大威胁。含有新德里金属-β-内酰胺酶 1 (NDM-1) 及其变体的肠杆菌科生物体能够水解几乎所有 β-内酰胺抗菌剂，包括碳青霉烯类药物，被称为超级细菌，分布于世界各地。尽管经过过去十年的努力，发现一种可以进入临床的 NDM-1 抑制剂仍然是一个挑战。在这里，我们使用非靶向代谢组学方法将氧化型谷胱甘肽 (GSSG) 鉴定为 blaNDM-1 的代谢生物标志物，并证明补充 GSSG 可以在体外和体内恢复携带 blaNDM-1 的大肠杆菌中的碳青霉烯类药物敏感性。我们发现，外源性 GSSG 通过干扰细胞内氧化还原稳态并抑制耐药大肠杆菌中 NDM-1 的表达来促进碳青霉烯类药物的杀菌作用。这项研究建立了一种基于代谢组学的策略，以增强代谢依赖性抗生素治疗耐药细菌的功效。