National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China.
College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China.
EMBO Mol Med. 2024 May;16(5):1051-1062. doi: 10.1038/s44321-024-00061-x. Epub 2024 Apr 2.
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.
携带质粒介导β-内酰胺酶基因的耐药肠杆菌科的出现，对公共卫生构成了重大威胁。肠杆菌科中含有新德里金属β-内酰胺酶-1（NDM-1）及其变体的生物体，能够水解几乎所有β-内酰胺类抗菌药物，包括碳青霉烯类，被称为超级细菌，并在全球范围内传播。尽管在过去十年中做出了努力，但发现一种能够达到临床应用的 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鉴定出氧化型谷胱甘肽（GSSG）作为 bla 的代谢生物标志物，并证明 GSSG 补充可以恢复携带 bla 的大肠杆菌在体外和体内对碳青霉烯类药物的敏感性。我们表明，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，促进碳青霉烯类药物的杀菌作用。本研究建立了一种基于代谢组学的策略，用于增强代谢依赖性抗生素的疗效，以治疗抗生素耐药菌。
